Introduction
Atherogenic lipoproteins are chylomicrons, VLDL, intermediate-density lipoproteins, LDL and lipoprotein (a) (Lp(a)). Each of these particles contains one molecule of apoB, which encircles the particle providing an external supportive skeleton within which the particle exists( Reference Anderson, Gregoire and Hegele 1 ). Since each particle contains one molecule of apoB, whether as apoB48 carried on intestinal chylomicron particles or apoB100 carried on hepatic lipoproteins, plasma apoB represents the number of all atherogenic apoB-lipoproteins. Of these, LDL make up by far the largest percentage (about 90 % on average), and therefore plasma apoB is driven by LDL apoB( Reference Lewis, Uffelman and Szeto 2 – Reference Ginsberg, Zhang and Hernandez-Ono 4 ). Plasma total cholesterol, non-HDL-cholesterol (non-HDL-C) and LDL-cholesterol (LDL-C) are all highly correlated with apoB and the risk of vascular disease increases exponentially as the concentrations of all four increase in plasma. However, the lipid content and therefore the size of all the apoB particles can vary substantially( Reference Sniderman, St-Pierre and Cantin 5 ).
In particular, LDL particles can contain an average mass of cholesterol or be cholesterol-enriched or cholesterol-depleted. When LDL particles are either cholesterol-enriched or cholesterol-depleted, LDL-C is an inaccurate measure of LDL number, particularly if plasma TAG is more than 1·5 mmol/l( Reference Anderson, Gregoire and Hegele 1 ). Hyperapobetalipoproteinaemia (or hyperapoB) was defined by Sniderman et al. ( Reference Sniderman, Shapiro and Marpole 6 ) in 1980 as a proatherogenic lipoprotein phenotype characterised by elevated numbers of apoB-lipoproteins but normal or near-normal plasma LDL-C. In this phenotype, the discordance between the LDL-C and apoB is due to cholesterol-depleted LDL particles. Of note, in contrast to plasma TAG used for the calculation of LDL-C in the Friedewald equation, plasma apoB can be measured in non-fasting samples( Reference Anderson, Gregoire and Hegele 1 ). A plasma apoB of ≥1·2 g/l, which is about the 75th percentile of plasma apoB concentrations in a Canadian population( Reference Connelly, Poapst and Davignon 7 ), identifies subjects with hyperapoB( Reference Holewijn, Sniderman and den Heijer 8 ).
Plasma apoB and CVD
Plasma apoB is a more accurate marker of cardiovascular risk than LDL-C or non-HDL-C( Reference Sniderman, Williams and Contois 9 ). A recent meta-analysis, comparing the number of clinical events prevented by different treatment strategies, revealed that over a 10-year period, a non-HDL-C strategy would prevent 300 000 more events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more events than a non-HDL-C strategy( Reference Sniderman, Williams and Contois 9 ). The measurement of plasma apoB was recommended in 2009 by the American Association for Clinical Chemistry Lipoproteins and Vascular Diseases Division Working Group on Best Practices as a more reliable indicator of risk than LDL-C( Reference Contois, McConnell and Sethi 10 ). It was also introduced to the Canadian dyslipidaemia guidelines in the same year as an alternative primary target of therapy( Reference Genest, McPherson and Frohlich 11 ) and continues to be recommended in the latest update of the guideline in 2014( Reference Anderson, Gregoire and Hegele 1 , Reference Anderson, Gregoire and Hegele 12 ). Particularly for subjects with intermediate CVD risk and/or insulin resistance, an apoB ≥1·2 g/l identifies patients at increased CVD risk who may benefit from pharmacotherapy despite a plasma LDL-C of <3·5 mmol/l( Reference Anderson, Gregoire and Hegele 1 ). Similarly in 2011, the European Atherosclerosis Society and European Society of Cardiology stated that non-HDL-C or apoB may better estimate the concentration of atherogenic particles than LDL-C, especially in high risk patients with diabetes or the metabolic syndrome( Reference Catapano, Reiner and De Backer 13 ). The recent 2013 guidelines of the American College of Cardiology and the American Heart Association, however, do not encompass the use of plasma apoB for the screening and treatment target for CVD( Reference Stone, Robinson and Lichtenstein 14 ). Since then a series of reports using discordance analysis have all shown that apoB is superior to either LDL-C or non-HDL-C to estimate cardiovascular risk( Reference Pencina, D’Agostino and Zdrojewski 15 , Reference Sniderman, Lamarche and Contois 16 ).
Plasma apoB and type 2 diabetes
Emerging clinical and epidemiological evidence also links hyperapoB to the development of type 2 diabetes (T2D), in addition to CVD, in humans. Both diseases are viewed as chronic inflammatory disease, and apoB-lipoproteins, primarily LDL, are known to induce multiple derangements in inflammatory cascades that lead to atherosclerosis( Reference Williams and Tabas 17 , Reference Fan and Watanabe 18 ). However, evidence from our laboratory( Reference Faraj, Messier and Bastard 19 ), as well as others( Reference Ridker, Rifai and Rose 20 – Reference Bermudez, Rifai and Buring 22 ), has shown that plasma apoB, not total cholesterol or LDL-C, correlates strongly with plasma inflammatory markers in human subjects. Moreover, in non-diabetic obese subjects, plasma apoB but not LDL-C correlates positively with dysfunctional white adipose tissue ex vivo and delayed plasma clearance of dietary fat, hyperinsulinaemia, insulin resistance and activation of the IL-1β system in vivo ( Reference Faraj, Messier and Bastard 19 , Reference Wassef, Bissonnette and Saint-Pierre 23 – Reference Bissonnette, Saint-Pierre and Lamantia 25 ), all of which are known risk factors for T2D. Epidemiological studies support that hyperapoB predicts the development of T2D before the onset of the disease by 3–10 years in Turkish( Reference Onat, Can and Hergenc 26 ), Canadian( Reference Ley, Harris and Connelly 27 ), Finnish( Reference Salomaa, Havulinna and Saarela 28 ) and South Korean( Reference Hwang, Ahn and Park 29 ) populations, independent of traditional risk factors such as central adiposity( Reference Onat, Can and Hergenc 26 , Reference Ley, Harris and Connelly 27 ), inflammation( Reference Onat, Can and Hergenc 26 ), fasting glucose and glycated Hb( Reference Ley, Harris and Connelly 27 , Reference Hwang, Ahn and Park 29 ).
Despite the central role of hyperapoB in the prediction and promotion of CVD and T2D and the inaccurate prediction of plasma apoB by lipids particularly in subjects with hyperlipidaemia, nutritional reviews and guidelines( Reference Genest, McPherson and Frohlich 11 ) for the treatment of dyslipidaemias have not addressed the regulation of apoB-particle number in plasma and focused mainly on their lipid content. Moreover, recent reviews on this topic mainly focused on the effect of dietary fatty acids (FA) and weight loss on plasma apoB-lipoproteins( Reference Lamarche and Couture 30 – Reference Chan, Barrett and Watts 32 ). Accordingly, we reviewed recent published literature (within the last 10 years) on the effects of multiple dietary interventions and components on plasma apoB and other parameters (VLDL-cholesterol (VLDL-C), LDL-C, non-HDL-C, TAG, apoA1 and apoB:apoA1). All human studies in an adult population (>18 years old) that were written in English and corresponded to the search criteria ‘diet and apoB’ on PubMed on 25 May 2015 were included. Genetic variations affecting plasma lipoprotein-related parameters are reported to affect the response efficiency to dietary interventions or components( Reference Gammon, Minihane and Kruger 33 – Reference Curti, Rogero and Baltar 36 ). However, as the present review aims to guide nutritional interventions targeting hyperapoB in clinical practice where data on the genetic background may not be readily available, studies examining specific gene–diet interactions were not included in this analysis. Given that the definitions of very-low- to high-carbohydrate (CHO) diets differ between studies, we used the definitions suggested by Feinman et al. ( Reference Feinman, Pogozelski and Astrup 37 ), mostly driven from the American Diabetic Association Guidelines, and unified the definitions for CHO intake throughout the eighty-seven studies examined. Very-low, low-, moderate- and high-CHO diets were those providing less than 10 %, 10–25 %, 26–45 % and >45 % of energy from CHO, respectively( Reference Feinman, Pogozelski and Astrup 37 ). Special emphasis was placed on data generated from randomised controlled trials (RCT) to determine the strength of evidence; however, prospective interventional and association studies were also included for completeness.
A comprehensive comparison of the eighty-seven studies included in the present review is provided in Table 1. When enough data were reported, the 95 % CI for the changes in plasma apoB and other lipoprotein parameters were calculated for the individual studies (Table 1). A table summarising the overall direction of changes in lipoprotein parameters based on the number of RCT supporting the findings is also provided (Table 2). Of note, the studies examined here that are summarised in Table 2 use data from the eighty-seven studies that examined plasma apoB in addition to other lipoprotein parameters to allow comparison between the parameters. Thus, the present review may not be comprehensive for the effect of the dietary components and patterns on plasma cholesterol, TAG and apoA1.
Summary of nutritional interventions affecting plasma apoB and other lipoprotein-related parametersFootnote *
↓, Significant decrease in the plasma parameter examined; ↑, significant increase in the plasma parameter examined; –, no significant effect; AMR101, eicosapentaenoic acid ethyl ester; CHO, carbohydrates; CLA, conjugated linoleic acid; cross-sect., cross-sectional study; CRP, C-reactive protein; DASH, Dietary Approaches to Stop Hypertension; dyslipid, dyslipidaemic; FA, fatty acids; FCR, fractional catabolic rate; HbA1c, glycated Hb; HDL-C, HDL-cholesterol; HFCS, high-fructose corn syrup; hyperchol, hypercholesterolaemic; hyperlipid, hyperlipidaemic; LDL-C, LDL-cholesterol; M, men; MCFA, medium-chain fatty acids; Med, Mediterranean; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; N/E, not examined; non-HDL-C, non-HDL-cholesterol; normolipid, normolipidaemic; MS, metabolic syndrome; P-OM3, prescription omega-3-acid ethyl esters; Pros, prospective intervention study; RCT, randomised controlled trial; Ref, reference; RESMENA, Reduction of the Metabolic Syndrome in Navarra-Spain; RLP, remnant-like particles; ROH, alcohol; RT, resistance training; T2D, type 2 diabetes; TRL, TAG-rich lipoproteins; VAT, visceral adipose tissue; VLDL-C, VLDL-cholesterol; W, women.
a Significant effect v. baseline; b significant effect v. control, placebo or other test diets. For cross-sectional studies, the effects were based on differences in group means. When more than two diets were compared, each diet was labelled by a letter to indicate the diets compared.
* The Table summarises the effects of each dietary component or intervention presented in the horizontal subtitles on plasma concentrations of apoB and other lipoprotein-related parameters.
† n Represents the number of subjects analysed in each study for plasma apoB, except when indicated as either enrolled or completed.
‡ Percentage macronutrient represents percentage of total daily energy intake of each nutrient. Percentages of energy intake from macronutrients were estimated, when necessary, using Atwater coefficients (4 kcal/g for carbohydrates and protein, 9 kcal/g for lipids). To convert energy intake to kJ, multiply by 4·184.
§ When enough data were provided, the effect size was calculated as a 95 % CI based on the change during the intervention in comparison with control, placebo or other test diets.
∥ Non-HDL-C refers to non-HDL-C, LDL-C and/or VLDL-C depending on the data provided in each paper. To convert cholesterol concentrations to mg/dl, multiply by 38·67.
¶ To convert TAG concentrations to mg/dl, multiply by 88·57.
Summary of the effects of dietary components and healthy dietary patterns on plasma apoB and lipoprotein parameters based on the original human studies examined in the present review
Non-HDL-C, non-HDL-cholesterol; HDL-C, HDL-cholesterol; ↓, majority of the studies reviewed (>50 %) reported a decrease; ↔, lack of effect, controversial findings (<50 % in agreement) or insufficient data (≤2 studies); CHO, carbohydrates; ↑, majority of the studies reviewed (>50 %) reported an increase; LDL-C, LDL-cholesterol; N/E, not examined; FA, fatty acids; DASH, Dietary Approaches to Stop Hypertension; VLDL-C, VLDL-cholesterol; RCT, randomised controlled trial.
* Non-HDL-C includes non-HDL-C, LDL-C and/or VLDL-C depending on the data provided.
† Marks the dietary component or pattern with consistent effect based on >3 RCT.
‡ Marks the dietary component or pattern with consistent effect based on 2–3 RCT.
§ Effects examined in subjects with the metabolic syndrome and/or dyslipidaemia only.
∥ Includes conclusions reported in a previous meta-analysis.
¶ Evidence derived from cross-sectional studies and association analysis.
Effect of hypoenergetic diet-induced weight loss on plasma apoB
Obesity promotes cardiometabolic disease, and weight loss as modest as 5–10 % has been reported to ameliorate the risks of T2D and CVD( Reference Tuomilehto, Lindstrom and Eriksson 38 – Reference Poobalan, Aucott and Smith 40 ). Hypoenergetic diet (about 5440–7110 kJ; 1300–1700 kcal)-induced weight loss of about 6–12 % was reported to decrease plasma apoB, whether on a low-fat/high-CHO diet (≤30 % fat; >45 % CHO)( Reference Feinman, Pogozelski and Astrup 37 , Reference Chan, Watts and Gan 41 , Reference Faraj, Lavoie and Messier 42 ), a higher-fat/moderate-CHO diet (>30 % fat; 26–45 % CHO)( Reference Feinman, Pogozelski and Astrup 37 , Reference Ng, Watts and Barrett 43 , Reference de la Iglesia, Lopez-Legarrea and Crujeiras 44 ) or when combined with resistance training (4 % weight loss)( Reference Valente, Sheehy and Avila 45 ). Similar effects were reported for a very-low-energy diet (2510–3350 kJ (600–800 kcal); 6 % weight loss)( Reference Vasudevan, Tchoua and Gillard 46 ). Reduction in plasma apoB is proposed to be due to the reduction in VLDL production rate and conversion to LDL and to the increase in LDL catabolic rate( Reference Ng, Watts and Barrett 43 ), and appears to mirror that of TAG particularly in subjects with dyslipidaemia or the metabolic syndrome. Addition of ezetimibe (a cholesterol-lowering agent) to a hypoenergetic diet did not have an additional benefit on plasma TAG and VLDL-apoB100 concentrations and secretion rates( Reference Chan, Watts and Gan 41 ). Moreover, increasing the frequency of meals in RESMENA dietary pattern (seven v. five meals/d) did not induce a further decrease in plasma apoB( Reference de la Iglesia, Lopez-Legarrea and Crujeiras 44 ). (Note that The RESMENA-S study (Reduction of the Metabolic Syndrome in Navarra-Spain) is an RCT comparing two hypoenergetic diets with an energy deficit of 30 % of requirements; the RESMENA dietary pattern has a macronutrient distribution of 40/30/30 (CHO/fat/protein) and high meal frequency (seven meals/d), while the control diet is based on the American Heart Association guideline and has a macronutrient distribution of 55/30/15 and a lower meal frequency (three to five meals/d)( Reference Chan, Watts and Gan 41 ).)
Of note, the effect of changes in fat depots on plasma apoB may be sex-dependent. In a 1-year study using a hypoenergetic diet combined with aerobic training in 107 obese men with dyslipidaemia, reduction in plasma apoB was dependent on the reduction in visceral adipose tissue( Reference Pelletier-Beaumont, Arsenault and Almeras 47 ). In a study by our group in fifty-six postmenopausal obese women, a 6-month hypoenergetic diet induced a reduction in plasma apoB that was independent of changes in adiposity or visceral adipose tissue but dependent on baseline apoB( Reference Faraj, Lavoie and Messier 42 ), which in turn was negatively associated with the diet quality( Reference Lavoie, Faraj and Strychar 48 , Reference Haghighatdoost, Sarrafzadegan and Mohammadifard 49 ).
Thus, in all four RCT and three prospective interventional studies examining 335 healthy or dyslipidaemic overweight and obese subjects in total, hypoenergetic diet-inducing weight loss (about 6–12 % alone or 4 % with resistance training) over 4–52 weeks induced a reduction in plasma apoB and TAG (six studies for TAG), with less consistent changes in non-HDL-C, LDL-C and HDL-C, and no data for VLDL-C( Reference Chan, Watts and Gan 41 – Reference Pelletier-Beaumont, Arsenault and Almeras 47 ). When examined, there was no effect on plasma apoA1 (four studies) and a decrease in plasma apoB:apoA1 (two studies) (Table 2). More studies are needed to evaluate whether sex differences exist in the regulation of plasma apoB by changes in body fat distribution, and to confirm whether plasma apoB:apoA1 is decreased with weight loss in overweight and obese subjects.
Effects of macronutrients on plasma apoB
Carbohydrates
Current Canadian and American guidelines for the prevention of chronic diseases recommend a balanced diet with 45–65 % CHO, 20–35 % fat and 10–35 % protein( 50 – 52 ). However, high CHO/low-fat-diets are associated with higher plasma total, VLDL- and chylomicrons-TAG in the fasting and postprandial states( Reference Stone, Robinson and Lichtenstein 14 , Reference Parks 53 ) and with higher apoB and Lp(a)( Reference Lichtenstein 54 – Reference Shin, Blanche and Rawlings 56 ). For example, switching 140 healthy men from 4 weeks on a moderate CHO (45 %)/high-fat (40 %) diet to 4 weeks on a high CHO (65 %)/low-fat-diet (20 %) with equivalent 50:50 ratio of simple to complex CHO, increased plasma apoB, TAG, Lp(a) as well as apoC-III (an inhibitor of lipoprotein lipase, whose activity is vital to hydrolyse and clear plasma TAG)( Reference Shin, Blanche and Rawlings 56 ) (Table 1). The effects of these diets on plasma apoB and TAG are believed to be primarily due to higher CHO flux to the liver increasing de novo lipogenesis and production of apoB-lipoproteins( Reference Parks and Hellerstein 57 ). Moreover, elevated TAG promotes cholesteryl ester transfer protein activity (CETP)( Reference Sacks 58 ), which favours the exchange of cholesterol on HDL and LDL particles with TAG on TAG-rich lipoproteins (TRL, namely VLDL and chylomicrons) and may explain lower plasma LDL-C and HDL-C with these diets( Reference Lichtenstein 54 – Reference Shin, Blanche and Rawlings 56 ).
Compared with high-CHO diets (49–65 %), moderate-CHO (26–45 %)/high-fat diets (38–46 %) were reported to improve plasma apoB, TAG and HDL-C but produced less consistent effects on plasma LDL-C( Reference Shin, Blanche and Rawlings 56 , Reference Krauss, Blanche and Rawlings 59 – Reference Mangravite, Chiu and Wojnoonski 62 ) (Table 1). Notably, compared diets within each study( Reference Shin, Blanche and Rawlings 56 , Reference Krauss, Blanche and Rawlings 59 – Reference Mangravite, Chiu and Wojnoonski 62 ) contained equivalent amounts of fibre (about 25–30 g/d) or equivalent simple:complex CHO ratio (50:50), excluding the confounding effects of these nutrients (as discussed in the Simple sugars and Dietary fibres sections below). The benefit of the reduction in CHO content, especially in regards to plasma apoB, appears to be dependent on the type of nutrient used to replace CHO. When the types of FA were compared concomitantly in a large RCT on 178 healthy overweight and obese men and compared with a high-CHO diet (54 % CHO), a moderate-CHO diet (26 % CHO) reduced plasma apoB (95 % CI –0·05, –0·16 g/l adjusted for weight) only in combination with a higher MUFA content (27 % MUFA, 9 % SFA, which also induced weight loss) not a higher SFA content (20 % MUFA, 15 % SFA)( Reference Krauss, Blanche and Rawlings 59 ). In line in a smaller cross-over RCT on forty healthy men, the reduction in CHO intake alone (50 % to 31 %) without a change in the percentage of fat, MUFA and SFA content (38, 15 and 15 %, respectively) did not affect plasma apoB( Reference Mangravite, Chiu and Wojnoonski 62 ). Plasma apoB was only reduced when MUFA content was increased to 21 % and that of SFA was decreased to 8 % in the same moderate-CHO diet (31 %)( Reference Mangravite, Chiu and Wojnoonski 62 ). Even within a high-CHO diet, a decrease in CHO content (55 to 50 %), accompanied by an increase in MUFA content (11 to 17 %) and equivalent amount of fibre, was reported to decrease plasma apoB, VLDL-C, TAG and increase HDL-C in hypercholesterolaemic men( Reference Mercanligil, Arslan and Alasalvar 63 ). Larger studies are needed to determine which nutritional component has the largest effect on plasma apoB: the reduction in CHO, the increase in MUFA, or the decrease in SFA intake.
Further restriction in CHO intake to less than 10 % in very-low-CHO diets does not appear to influence plasma apoB, particularly when with high SFA intake usually associated with these diets (about 20 %) despite additional benefits on plasma TAG and HDL-C( Reference Brinkworth, Noakes and Buckley 64 , Reference Tay, Brinkworth and Noakes 65 ) (Table 1). This may explain why compared with the very-low-CHO Atkins diet (58 % fat; 30 % SFA), weight maintenance for 4 weeks on the very-high-CHO Ornish diet (9 % fat; 3 % SFA) decreased plasma apoB (95 % CI –0·03, –0·19 g/l)( Reference Miller, Beach and Sorkin 66 ). Notably, lowering SFA intake is also reported to increase flow-mediated vasodilatation (i.e. a measure of endothelial function)( Reference Keogh, Grieger and Noakes 67 ), which may add to the benefits of low-SFA diets.
Thus, in all four RCT and two prospective interventional studies examined including 452 subjects in total, plasma apoB was consistently reduced in healthy or hyperlipidaemic subjects with isoenergetic diets composed of 26–50 % CHO, 36–46 % fat, 14–32 % protein, 11–27 % MUFA, 5–14 % PUFA and 7–13 % SFA consumed over 3–4 weeks only( Reference Shin, Blanche and Rawlings 56 , Reference Krauss, Blanche and Rawlings 59 – Reference Mercanligil, Arslan and Alasalvar 63 ). Plasma TAG and HDL-C were also improved, while inconsistent or insufficient data were observed for non-HDL-C, LDL-C, VLDL-C and apoA1. None of the studies evaluated plasma apoB:apoA1 (Table 2). The macronutrient composition of these six studies( Reference Shin, Blanche and Rawlings 56 , Reference Krauss, Blanche and Rawlings 59 – Reference Mercanligil, Arslan and Alasalvar 63 ) was used to generate the summary of the isoenergetic diets observed to reduce plasma apoB (reported in the Abstract and Conclusion).
Simple sugars
The American Heart Association recently issued a strict recommendation to limit the intake of added sugars to 630 and 420 kJ/d (150 and 100 kcal/d) for men and women, respectively (about 6–7 % of total energy)( Reference Johnson, Appel and Brands 68 ). The Dietary Intake Reference for Canadians remains more permissive with a maximal intake of ≤25 % of total energy( Reference Hellwig, Otten and Meyers 51 ). However, neither guideline distinguishes between the types of simple sugars. Compared with glucose, fructose intake is known to be a poor stimulant of insulin secretion due to the low expression of its receptor, GLUT5, in the pancreas( Reference Swarbrick, Stanhope and Elliott 69 ). A high-fructose diet decreases hepatic insulin sensitivity and raises de novo lipogenesis and plasma TAG, effects which hinder hepatic degradation of apoB and enhance VLDL secretion( Reference Semenkovich 70 ).
Human research on the differential effects of fructose and glucose on plasma apoB is limited to two non-RCT studies (55 % CHO, 30 % fat and 15 % protein), small sample size (n 7–48) and short duration (2–10 weeks) (Table 1). Nevertheless, their results are consistent with present knowledge on the negative effects of fructose metabolism on plasma apoB and postprandial TAG( Reference Swarbrick, Stanhope and Elliott 69 , Reference Stanhope, Bremer and Medici 71 ). In addition, increased fasting glucose and decreased postprandial insulin secretion were also reported in one study with fructose v. glucose intake( Reference Swarbrick, Stanhope and Elliott 69 ). Notably, however, both studies used 25 % of energy from fructose alone( Reference Swarbrick, Stanhope and Elliott 69 , Reference Stanhope, Bremer and Medici 71 ), which may not represent usual intake. More RCT are needed to determine the effect of habitual fructose intake on plasma apoB, apoB:apoA1 and other lipoprotein-related parameters.
Dietary fibres
Epidemiological and clinical studies suggest that high intake of dietary fibre is associated with reduced risk of T2D and CVD( Reference Lattimer and Haub 72 ). Soluble fibres, such as psyllium, reduce the reabsorption of bile acids, thus increasing cholesterol excretion( Reference Theuwissen and Mensink 73 ). Moreover, in guinea-pigs, psyllium was reported to decrease the secretion of VLDL particles and their conversion to LDL, and to enhance VLDL and LDL apoB turnover by increasing hepatic LDL receptor expression( Reference Fernandez, Vergara-Jimenez and Conde 74 ). Soluble fibre consumption up to 10–25 g/d is recommended for hypercholesterolaemic patients by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)( 75 ) as it consistently lowers LDL-C( Reference Shrestha, Volek and Udani 76 – Reference Comerford, Artiss and Jen 79 ). It has, however, little, if any, effect on plasma TAG and HDL-C( Reference Shrestha, Volek and Udani 76 – Reference Comerford, Artiss and Jen 79 ).
Human research examining the effect of dietary fibres on plasma apoB is limited to four RCT, the results of which are, however, promising (Table 1). One RCT reported that psyllium soluble fibre (7·68 g/d), in combination with plant sterols (2·6 g/d), decreased plasma apoB in subjects with hypercholesterolaemia( Reference Shrestha, Volek and Udani 76 ) due to reduction in intermediate-density lipoprotein and LDL numbers. Interestingly, there was also a reduction in small HDL particles possibly adding to the anti-atherogenic effects of this diet. Similarly, cocoa cream enriched with hazelnuts, phytosterols (2 g/d) and soluble fibre (20 g/d) reduced plasma apoB100 and LDL-C compared with a control cocoa cream in hypertensive and hypercholesterolaemic subjects( Reference Sola, Valls and Godas 78 ). Concordant results were drawn from another RCT where the addition of Metamucil (11 g/d psyllium soluble fibre) to simvastatin therapy (10 mg, cholesterol-lowering agent) had a similar hypocholesterolaemic effect as a higher dose of simvastatin (20 mg)( Reference Moreyra, Wilson and Koraym 77 ). Soluble fibres also include α-cyclodextrin, which is derived from maize and is known to form a complex with dietary fat, reducing its bioavailability. In contrast to psyllium, no effect of α-cyclodextrin intake was observed on plasma apoB in one RCT on healthy subjects despite lower plasma LDL-C( Reference Comerford, Artiss and Jen 79 ).
Thus, in all three out of four RCT conducted on dyslipidaemic subjects (n 214 in total) and ranging from 4 to 8 weeks, the intake of soluble fibre (about 8–20 g psyllium) on a dietary background of 44–50 % CHO, 36–41 % fat and 15–17 % protein reduced plasma apoB and LDL-C but did not affect TAG( Reference Shrestha, Volek and Udani 76 – Reference Comerford, Artiss and Jen 79 ). Less consistent or no data exist for VLDL-C, HDL-C, apoA1 and apoB:apoA1 (note that the macronutrient composition of these diets fits within the range reported to reduce plasma apoB in the Abstract and Conclusion). More RCT are needed to examine the independent effects of the quantity and/or types of soluble fibres on plasma apoB and apoB:apoA1.
Lipids
MUFA and PUFA v. SFA
High intake of SFA is known to increase plasma total, LDL-C and HDL-C and to be associated with a higher risk of cardiometabolic disease compared with the intake of unsaturated fats( Reference Lichtenstein 54 ). Current FAO/WHO guidelines limit SFA intake to less than 10 % of total energy, with the remaining fat sources as PUFA (6–11 %) or MUFA( 80 ). Notably, the higher limit of PUFA at <11 % was set as the risk for lipid peroxidation may increase with higher intake, particularly when tocopherol (vitamin E) intake is low( 80 ).
A meta-analysis on twenty-five RCT( Reference Mozaffarian and Clarke 81 ) together with four more recent RCT and a controlled parallel trial confirmed that decreasing SFA intake by increasing MUFA intake lowers plasma apoB and LDL-C, but are less consistent in regards to plasma TAG, HDL-C, apoA1 and apoB:apoA1( Reference Mangravite, Chiu and Wojnoonski 62 , Reference Jebb, Lovegrove and Griffin 82 – Reference Bos, de Vries and Feskens 86 ) (Table 1). In the largest RCT on 548 individuals at high risk of the metabolic syndrome, 24 weeks on a high-MUFA diet (16 %) decreased plasma apoB compared with an isoenergetic diet with high-SFA (16 %) on a similar moderate-CHO (about 42–45 %) and -fat (36–38 %) backgrounds( Reference Jebb, Lovegrove and Griffin 82 ). Of note, however, an even greater effect of a combination of low fat (26–28 %) and low SFA (8–9 %) was observed on plasma apoB in that study that counterbalanced the effect of higher CHO (about 51–52 %), suggesting that lowering SFA intake is key( Reference Jebb, Lovegrove and Griffin 82 ). Similar effects were also observed in eighty-five dyslipidaemic subjects at risk for T2D within high-CHO diets, where a high-CHO (55 %)/low-fat (29 %)/low-SFA (8 %) diet did not increase plasma apoB when compared with a lower-CHO (49 %)/high-fat (36 %)/high-SFA (16 %) diet with similar MUFA (16 and 14 %) and PUFA (6 %) backgrounds( Reference Berglund, Lefevre and Ginsberg 83 ), underlying the effects of low SFA. This further underscores the need for head-to-head comparison between the specific effects of CHO, SFA and MUFA on plasma apoB. The beneficial effects of replacing SFA by MUFA were also observed in healthy men following a moderate-CHO diet (31 %)( Reference Mangravite, Chiu and Wojnoonski 62 ), in healthy subjects following a high-CHO diet (48 %)( Reference Allman-Farinelli, Gomes and Favaloro 84 ), in subjects at risk for T2D following a high-CHO diet (49 %)( Reference Berglund, Lefevre and Ginsberg 83 ), and in healthy abdominally obese subjects following moderate- to high-CHO diets (41 and 46 % CHO; 95 % CI –0·09, –0·21 and –0·03, –0·17 g apoB/l, respectively)( Reference van Dijk, Feskens and Bos 85 , Reference Bos, de Vries and Feskens 86 ). Finally, in the same meta-analysis by Mozaffarian & Clarke( Reference Mozaffarian and Clarke 81 ) on twenty-five RCT, while isoenergetic replacement of SFA by PUFA reduced plasma apoB, LDL-C and HDL-C, and induced a greater reduction in LDL-C than MUFA, the two types of unsaturated FA had similar effects on plasma apoB. This is also in line with another RCT on hypercholesterolaemic subjects( Reference Binkoski, Kris-Etherton and Wilson 87 ). No additional studies were found on the effect on PUFA on plasma apoB except for those examined in the section on n-3 PUFA.
A recent review on lipoprotein kinetics in humans suggests that the intake of SFA increases the pool size of LDL-apoB100 particles by decreasing their fractional catabolic rate( Reference Lamarche and Couture 30 ). SFA may also be linked to cardiometabolic risk through the activation of inflammatory cascades via Toll-like receptors 2 and 4 and the NF-κB-dependent pathway in murine and human cells, as reviewed( Reference Lee, Zhao and Hwang 88 ). This is believed to promote systemic inflammation and insulin resistance, both of which are known to reduce insulin-mediated degradation of apoB by the liver and TRL clearance by adipose tissue( Reference Semenkovich 70 , Reference Flock, Green and Kris-Etherton 89 ). SFA can also amplify lipopolysaccharide response by promoting the generation of ceramides that activate protein kinase C–ζ and mitogen-activated protein kinases in monocytes( Reference Schwartz, Zhang and Karnik 90 , Reference Chait and Kim 91 ). Reducing SFA intake is associated with an increase in the expression of LDL receptors on mononuclear cells in humans, promoting LDL uptake( Reference Flock, Green and Kris-Etherton 89 , Reference Mustad, Etherton and Cooper 92 ). It should be noted, however, that the association of SFA intake with chronic inflammation in humans remains controversial and may be dependent on the inflammatory marker examined( Reference Santos, Oliveira and Lopes 93 , Reference Teng, Chang and Chang 94 ). A recent systemic analysis reported that, while positive associations were found between SFA intake with soluble intercellular adhesion molecule-1 and IL-6, no significant association or insufficient data were found with other markers such as E-selectin, TNFα and C-reactive protein( Reference Santos, Oliveira and Lopes 93 ).
In summary, in four RCT and one controlled parallel trial examined in the present review including 737 healthy or dyslipidaemic subjects, a consistent beneficial effect of reducing SFA intake (from 19 % to 8 %) by increasing MUFA intake (from 10 % to 21 %) was observed on plasma apoB and LDL-C using diets composed of 31–51 % CHO, 26–40 % fat and 11–32 % protein( Reference Mangravite, Chiu and Wojnoonski 62 , Reference Jebb, Lovegrove and Griffin 82 – Reference Bos, de Vries and Feskens 86 ). These findings support an earlier meta-analysis published to date( Reference Mozaffarian and Clarke 81 ). Plasma HDL-C was reduced with these diets, probably a reflection of the reduction in plasma cholesterol, while less consistent or insufficient data exist for VLDL-C, TAG, apoA1 and apoB:apoA1 in these studies( Reference Mangravite, Chiu and Wojnoonski 62 , Reference Jebb, Lovegrove and Griffin 82 – Reference Bos, de Vries and Feskens 86 ). Of note, in addition to the six diets in the section on CHO (Carbohydrates section), the macronutrient composition of the five studies examined here were used to generate the summary of the isoenergetic diets observed to reduce plasma apoB (reported in the Abstract and Conclusion).
Marine- and plant-derived n-3 PUFA
Fish oil and n-3 FA found in fish oil, EPA and DHA, have been reported to improve dyslipidaemia, inflammation, insulin resistance and hepatic steatosis in mice and humans( Reference Cave, Hurt and Frazier 95 , Reference Bays, Tighe and Sadovsky 96 ). The American Heart Association recommends fish consumption, at least two servings per week, or fish oil supplementation to reduce the risk of CVD( Reference Kris-Etherton, Harris and Appel 97 ). Similarly, the Canadian Cardiovascular Society Guidelines indicates that the intake of n-3 FA (2–4 g/d of both EPA and DHA), under a physician’s care, can lower plasma TAG by 25–30 % in patients with hypertriacylglycerolaemia( Reference Anderson, Gregoire and Hegele 1 ). Increasing n-3 FA intake decreases plasma TAG and frequently VLDL-C, but rarely affects LDL-C and HDL-C( Reference Bays, Ballantyne and Kastelein 98 – Reference Wong, Chan and Barrett 104 ).
Reduction in plasma apoB and TAG has been reported by all four RCT and one parallel trial reviewed using marine-derived n-3 FA supplementation (3·2 and 3·4 g/d of EPA:DHA at a 1·2:1 ratio( Reference Davidson, Stein and Bays 99 , Reference Wong, Chan and Ooi 103 , Reference Wong, Chan and Barrett 104 ) or 4 g/d EPA alone( Reference Bays, Ballantyne and Kastelein 98 )) or high fish intake (1·1–1·7 g n-3 FA/d)( Reference Zhang, Wang and Li 101 , Reference Ooi, Lichtenstein and Millar 105 ), for 6–24 weeks in hyperlipidaemic subjects not taking hypolipidaemic agents (Table 1). Less consistent effects have been reported for LDL-C, VLDL-C, non-HDL-C and HDL-C and insufficient data exist for apoA1 or apoB:apoA1 in these studies. When added to statins (i.e. cholesterol-lowering agents), P-OM3 (prescription omega-3-acid ethyl esters; 3·4 g/d; EPA:DHA at a 1·2:1 ratio) further decreased plasma apoB in hyperlipidaemic patients, when simvastatin (40 mg; n 254)( Reference Davidson, Stein and Bays 99 ) not atorvastatin (10–40 mg/d; n 219)( Reference Bays, McKenney and Maki 100 ) was used. However, it is reported that atorvastatin induces a greater reduction in plasma apoB than simvastatin( Reference Forster, Stewart and Bedford 106 , Reference Karalis, Ross and Vacari 107 ), which may limit additional benefits of the n-3 FA. Using a cross-over design, modulating the ratio of n-6:n-3 in a diet supplemented with 2·2 g/d marine-derived n-3 FA had no effect on plasma apoB in eleven hypercholesterolaemic subjects on statin treatment( Reference Lee, Dart and Walker 102 ).
Kinetics studies have demonstrated that the reduction in plasma TAG and apoB by n-3 FA in human subjects is mainly due to the reduction in the production rate of apoB100 and apoB48 TRL( Reference Wong, Chan and Ooi 103 – Reference Ooi, Lichtenstein and Millar 105 ), as recently reviewed( Reference Lamarche and Couture 30 – Reference Chan, Barrett and Watts 32 ). When combined with weight loss, n-3 FA induce a greater reduction in fasting apoB48 production rate and postprandial apoB48 concentrations( Reference Wong, Chan and Barrett 104 ). As secretion of TRL-TAG and TRL-apoB are closely linked, decreased TRL apoB100 secretion may be due to the inhibition of enzymes involved in TAG synthesis such as diacylglycerol acyltransferase and FA synthase, suppression of sterol regulatory element binding protein-1c gene transcription, and activation of β-oxidation( Reference Ooi, Lichtenstein and Millar 105 , Reference Watts, Chan and Ooi 108 ). In addition, both n-3 FA and n-6 PUFA favour hepatic apoB degradation in the post-endoplasmic reticulum pre-secretory proteolysis pathway through reactive oxygen species-induced autophagy( Reference Pan, Maitin and Parathath 109 ).
Observational studies also support that higher intakes of plant-derived n-3 FA (α-linolenic acid), but not plasma levels( Reference Pan, Chen and Chowdhury 110 ), are significantly associated with moderately lower risk of CVD( Reference Kris-Etherton, Harris and Appel 97 , Reference Pan, Chen and Chowdhury 110 ). The use of vegetable oils is encouraged to increase the intake of α-linolenic acid up to 0·6–1·2 % of total energy, the acceptable macronutrient distribution range established by the Institute of Medicine( 111 ). While few studies have examined the effect of plant-derived n-3 FA on apoB, a recent RCT on 179 healthy postmenopausal women reported that the intake of 40 g/d of flaxseeds with high α-linolenic acid compared with an equal amount of wheat germ had a small but modest benefit on plasma apoB (95 % CI –0·00, –0·09 g/l; Table 1)( Reference Dodin, Cunnane and Masse 112 , Reference Dodin, Lemay and Jacques 113 ). However, the conversion of plant- into marine-derived n-3 FA is at less than 1 %( Reference Brenna, Salem and Sinclair 114 ) and the mechanism by which α-linolenic acid benefits cardiometabolic health in humans may not involve plasma lipids and apoB.
In summary, for all four RCT and one parallel study conducted mostly on hyperlipidaemic subjects (n 411 in total) and ranging from 6 to 24 weeks, the intake of marine-derived n-3 FA, from oily fish (1·1–1·7 g/d) or supplementation (3·2–3·4 g/d EPA and DHA or 4 g/d EPA alone) reduced plasma apoB and TAG with less consistent benefits or insufficient data on the other lipids( Reference Bays, Ballantyne and Kastelein 98 , Reference Zhang, Wang and Li 101 , Reference Wong, Chan and Ooi 103 – Reference Ooi, Lichtenstein and Millar 105 ). Insufficient data also exist for the additional benefit of n-3 FA in combination with statins (two RCT; n 473) (note that not all studies reported the macronutrient or FA composition of the background diets to provide their summary). More RCT examining the additional effects of n-3 FA in combination with hypolipidaemic agents on plasma apoB and the apoB:apoA1 ratio are needed.
Trans-fatty acids
A higher consumption of trans-FA from industrial partially hydrogenated fats, a characteristic of the Western diet with high intake of processed food, is associated with higher risk of CVD( Reference Ooi, Ng and Watts 31 ). Isoenergetic substitution of trans-FA by SFA reduces plasma apoB and apoB:apoA1 and increases HDL-C and apoA1, as reported in a meta-analysis of thirteen trials( Reference Mozaffarian and Clarke 81 ). Only two more recent RCT were found, in both of which decreasing trans-FA (from 7·5 and 4·3 % to <0·5 %) by increasing cis-PUFA( Reference Vega-López, Matthan and Ausman 115 ) or cis-MUFA( Reference Wanders, Brouwer and Siebelink 116 ) also led to a decrease in plasma apoB. Trans-FA increase the pool size of LDL apoB100 by decreasing their fractional catabolic rate, but have no effect on VLDL apoB100( Reference Lamarche and Couture 30 ).
Trans-FA can also be produced naturally during the biohydrogenation of dietary PUFA by anaerobic bacteria in the rumen, and thus exist in small amounts (about 2–5 %) in meat and dairy products derived from ruminants( Reference Martin, Milinsk and Visentainer 117 ). Contradictory findings exist regarding the impact of natural trans-FA on CVD risk; while observational studies found no association( Reference Brouwer, Wanders and Katan 118 ), a cross-over trial reported that a diet high in conjugated linoleic acids and naturally occurring double-bonds increased plasma apoB and LDL-C and decreased HDL-C compared with a high-MUFA diet( Reference Wanders, Brouwer and Siebelink 116 ). Contradictory findings also exist as to whether industrial trans-FA have a higher( Reference Wanders, Brouwer and Siebelink 116 ) or a lower( Reference Chardigny, Destaillats and Malpuech-Brugere 119 ) impact on plasma apoB than natural trans-FA. However, sex-specific effects of natural trans-FA on increasing plasma LDL-C, HDL-C, apoB and apoA1 in women but not in men have been reported and may need to be accounted for in future studies( Reference Chardigny, Destaillats and Malpuech-Brugere 119 ).
Of importance to note is that, in 2007, Health Canada recommended that the content of trans-FA in vegetable oils and soft, spreadable margarines should be limited to 2 % of the total fat, while that of all other foods including ingredients sold to restaurants should be limited to 5 %. It also gave the food industry a 2-year window to achieve these recommendations( 120 ). This strategy appears to have achieved a positive impact, as the Canadian consumption of trans-FA has declined by 40 % over the past decade (from 8·4 to 4·9 g/d)( 120 ). Moreover, in June 2015, the US Food and Drug Administration removed partially hydrogenated oils, the main source of artificial trans-FA in processed foods, from the ‘generally recognized as safe’ list and gave food manufacturers 3 years to remove them from their products( 121 ). The current recommendation to promote cardiovascular health by both the American( 52 ) and the Canadian( Reference Hellwig, Otten and Meyers 51 ) guidelines is to reduce trans-FA to the least possible. This is also in line with the recommendation of the WHO of <1 % of total energy per d( 120 ). Thus, while plasma apoB was increased in the two RCT examined, the amounts of trans-FA used (4·3 % or about 11 g/d( Reference Vega-López, Matthan and Ausman 115 ) and 7·5 % or about 20 g/d( Reference Wanders, Brouwer and Siebelink 116 )) are unlikely to represent current habitual intake.
Medium-chain fatty acids
Medium-chain FA (MCFA) contain 6–12 carbons. Unlike long-chain FA, MCFA are usually absorbed directly into the portal circulation without the need for being incorporated in the chylomicron particles. Accordingly, oil made from MCFA is prescribed to treat patients with familial hyperchylomicronaemia( Reference Rouis, Dugi and Previato 122 ).
Only two studies with limited sample size (n 28 and 51) and duration (4 and 12 weeks) were reported on the effect of MCFA on plasma apoB in human subjects. Nevertheless, both studies reported no effect of high MCFA intake, as pure oil (20 g/d) or milk fat (8·5 v. 6·9 g/d), on fasting or postprandial plasma apoB, TAG, LDL-C, VLDL-C or apoA1( Reference Tremblay, Lamarche and Labonte 123 , Reference Bohl, Bjornshave and Rasmussen 124 ) in subjects with abdominal obesity alone( Reference Bohl, Bjornshave and Rasmussen 124 ) or with secondary hypertriacylglycerolaemia( Reference Tremblay, Lamarche and Labonte 123 ). No data were reported on plasma apoB:apoA1 in either study. These findings are also in line with the lack of an effect of MCFA on apoB reported in a recent review on the effect of dietary FA on lipoprotein metabolism( Reference Lamarche and Couture 30 ). As MCFA are suggested to increase fat oxidation( Reference Rego Costa, Rosado and Soares-Mota 125 ), more RCT comparing different types and higher doses of MCFA (with attention to possible gastrointestinal symptoms) or in combination with weight-loss intervention may be needed.
Dietary cholesterol
The impact of dietary cholesterol on plasma lipids and CVD risk remains controversial. To reduce the risk of CVD, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends limiting the intake of dietary cholesterol to 200 mg/d for subjects with hyperlipidaemia( 75 ). However, the recent American Heart Association/American College of Cardiology guidelines to reduce CVD concluded that there is insufficient evidence to determine whether lowering cholesterol intake reduces LDL-C( Reference Eckel, Jakicic and Ard 126 ). Studies examining the specific effect of cholesterol on plasma apoB are also scarce and limited in size( Reference Cesar, Oliveira and Mesquita 127 , Reference Pearce, Clifton and Noakes 128 ). Consumption of a high-cholesterol diet (804 mg/d; three eggs/d) in twenty-five normolipidaemic healthy young men increased plasma LDL-C, HDL-C and apoB, without affecting plasma TAG, apoA1 and Lp(a) compared with a low-cholesterol diet( Reference Cesar, Oliveira and Mesquita 127 ). In contrast in patients with T2D or prediabetes (42 % on lipid-lowering medications), consumption of a high- or low-cholesterol (590 v. 228 mg/d)/hypoenergetic/high-protein diet led to similar reductions in weight and plasma apoB, non-HDL-C, TAG, glucose, and insulin and blood pressure, whereas only the high-cholesterol diet led to an increase in HDL-C( Reference Pearce, Clifton and Noakes 128 ). However, weight loss and improved insulin sensitivity on both diets may have masked the effects of high cholesterol per se on plasma apoB. More RCT are needed to determine the independent effect of dietary cholesterol on plasma apoB and apoB:apoA1.
Phytosterols
Phytosterols are plant-derived steroid compounds similar in structure and function to cholesterol( Reference AbuMweis, Marinangeli and Frohlich 129 ). Current recommendations for hyperlipidaemic patients( 75 ) include 2 g/d of phytosterols, which is known to reduce LDL-C( Reference Demonty, Ras and van der Knaap 130 , Reference Abumweis, Barake and Jones 131 ). Dietary sources of phytosterols include vegetable oils, cereals and nuts and provide about 300 mg/d, as reported in a British population( Reference Klingberg, Andersson and Mulligan 132 ). Only three RCT explored the effects of phytosterol-enriched foods in subjects with the metabolic syndrome( Reference Sialvera, Pounis and Koutelidakis 133 ), hypertension and/or hypercholesterolaemia (n 254 in total)( Reference Shrestha, Volek and Udani 76 , Reference Sola, Valls and Godas 78 ). All three RCT reported a consistent improvement in plasma apoB and LDL-C when phytosterols were added to a yogurt drink (4 g/d)( Reference Sialvera, Pounis and Koutelidakis 133 ), a cocoa–hazelnut cream (2 g/d)( Reference Sola, Valls and Godas 78 ) or in combination with soluble fibres (7·68 g/d psyllium and 2·6 g/d phytosterols( Reference Shrestha, Volek and Udani 76 )). It is thus not possible to isolate an independent effect of phytosterol alone in these RCT. Of note, the background dietary composition of the phytosterol-enriched diets was 37–50 % CHO, 36–44 % fat and 15–17 % proteins, which is within the range observed to reduce plasma apoB (reported in the Abstract and Conclusion). More studies are needed to confirm the effect of phytosterols per se on plasma apoB and other lipids.
Proteins
Soya proteins
Following the publication of a meta-analysis supporting the negative association of soya protein intake with plasma cholesterol( Reference Anderson, Johnstone and Cook-Newell 134 ), the US Food and Drug Administration permitted the food industry to claim that ‘25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease’( 135 ). Soya proteins are reported to increase the clearance of apoB-lipoproteins by enhancing the synthesis of bile acid, increasing LDL receptor activity, and reducing hepatic particle secretion( Reference Potter 136 , Reference Baum, Teng and Erdman 137 ). On the other hand, increased insulin growth factor binding protein-3 has also been reported with soya protein intake, which suggests reduced bioavailability of insulin growth factor-1 and increased CVD risk( Reference Campbell, Khalil and Payton 138 ).
Eight RCT explored the impact of isolated soya proteins, in comparison with isolated milk proteins, on plasma apoB and lipids and their findings are inconsistent. Replacement of isolated milk proteins by isolated soya proteins (25–30 g/d) reduced plasma apoB, LDL-C and non-HDL-C in hypercholesterolaemic or hyperlipidaemic patients without( Reference Maki, Butteiger and Rains 139 ) or with haemodialysis( Reference Chen, Ferng and Yang 140 , Reference Chen, Chen and Yang 141 ), but had no effect on plasma LDL-C or apoB in normolipidaemic subjects( Reference Chen, Ferng and Yang 140 ). However, accumulation of isoflavones due to lack of renal excretion and unavailability of isoflavones for dialysis have been reported, which may limit the applicability of the results( Reference Fanti, Sawaya and Custer 142 ). In contrast, no benefits on plasma apoB were reported in healthy men( Reference Santo, Santo and Browne 143 – Reference McVeigh, Dillingham and Lampe 145 ) or patients with diet-controlled T2D( Reference Pipe, Gobert and Capes 146 ) consuming isolated soya proteins in comparison with isolated milk proteins, nor in healthy subjects supplemented with black soya peptide in comparison with casein( Reference Kwak, Ahn and Park 147 ). On the other hand, an RCT in hypercholesterolaemic postmenopausal women reported an increase in plasma apoB, which was, however, accompanied by an increase in weight with both soya and casein proteins( Reference Campbell, Khalil and Payton 138 ).
It should be noted, however, that an interaction was identified between plasma apoB and equol urinary excretion status( Reference Pipe, Gobert and Capes 146 ). Equol is a type of isoflavone produced endogenously in the intestine, which not all humans have the ability to synthesise( Reference Axelson, Kirk and Farrant 148 , Reference Setchell, Brown and Lydeking-Olsen 149 ). It has a greater oestrogen receptor-binding affinity and antioxidant capacity than other types of isoflavones. This may add to the inter-subject variability in the response to isoflavones. Moreover, as isoflavones are known to bind oestrogen receptors( Reference Barton 150 ), sex differences may also need to be explored. In addition to isoflavones, soya protein isolates contain other components such as saponins, phytic acid and trypsin inhibitors, which are biologically active molecules that may influence lipid profile( Reference Potter 136 ). While the specific effect of isoflavones on plasma apoB and lipids is yet to be demonstrated( Reference Santo, Santo and Browne 143 – Reference McVeigh, Dillingham and Lampe 145 ), that of the other components have not yet been examined.
Finally, the effect of non-soya protein was also examined in one RCT in comparison with casein protein in thirty-eight hypercholesterolaemic subjects. The intake of 25 g/d of cowpea protein isolate was reported to decrease plasma apoB, non-HDL-C and LDL-C and to increase plasma HDL-C( Reference Frota, dos Santos and Ribeiro 151 ).
In summary, inconsistent findings were observed in eight RCT (n 341; 4–52 weeks) examining the effect of replacing isolated milk proteins or casein with soya proteins on plasma apoB and lipids( Reference Campbell, Khalil and Payton 138 – Reference Kwak, Ahn and Park 147 ). However, three out of the four RCT conducted with 121 hyperlipidaemic subjects reported a decrease in plasma apoB and LDL-C with the intake of 25–30 g/d isolated soya protein over 4–12 weeks. More RCT are needed to confirm whether the effects of soya proteins are specific to subjects with hyperlipidaemia, are restricted to a specific soya protein component (i.e. isoflavones) or include other non-soya legume proteins.
Whey proteins
Milk proteins comprise a soluble fraction named whey and an insoluble fraction named casein( Reference Pereira 152 ). Whey proteins are recognised as immunomodulators, antioxidants and nutrient carriers (FA, retinol and Fe). Studies on the effect of whey proteins on lipid metabolism are scarce. However, consumption of 60 g/d whey protein, compared with an equal amount of casein, on a similar background diet of milk fat (63 g/d) with low or high MCFA reduced postprandial apoB48 in fifty-one subjects with abdominal obesity, an effect that remained significant after adjustment for age, sex, blood pressure, statin intake and weight change( Reference Bohl, Bjornshave and Rasmussen 124 ). More RCT are needed to explore the effect of whey protein v. casein or other types of proteins on lipoprotein profile in healthy and hyperlipidaemic subjects.
Alcohol
The Canadian Low-Risk Alcohol Drinking Guidelines recommend moderate alcohol consumption, defined as less than fifteen drinks for men and ten drinks for women per week( Reference Butt, Beirness and Gliksman 153 ). The protective effect of alcohol consumption, ranging from low to high, on plasma HDL-C was reported in the Atherosclerosis Risk in Communities (ARIC) cross-sectional study in 8932 middle-aged subjects( Reference Volcik, Ballantyne and Fuchs 154 ). In contrast, only low-to-moderate alcohol consumption (about 1·5 drinks/d), compared with lack of, was associated with a lower plasma apoB and TAG in that study, and the effect was limited to wine drinkers who were also white women( Reference Volcik, Ballantyne and Fuchs 154 ). In another cross-sectional study in 2907 Swedish adults, total ethanol intake (about one drink/d) correlated with lower plasma apoB in women only and higher HDL in all subjects after adjustment for multiple confounders( Reference Tognon, Berg and Mehlig 155 ). In the larger Third National Health and Nutrition Examination Survey (NHANES III) study on 8708 adults, plasma apoB decreased across the quartiles of higher alcohol consumption (>2 and 1–2 drinks/d), although no adjustment was made for potential confounders such as the types of alcohol or sex( Reference Liangpunsakul, Qi and Crabb 156 ). In contrast, in a smaller cross-sectional study on 636 postmenopausal women, alcohol consumption was not associated with plasma apoB per se but with a lower plasma apoB:apoA1 ratio( Reference Simonsson, Schmidt and Sigurdadottir 157 ).
Heavy alcohol consumption promotes alcoholic fatty liver disease, elevated hepatic apoB mRNA and higher plasma TAG( Reference Kawata, Fukuda and Inui 158 , Reference Klop, do Rego and Cabezas 159 ). This may explain why in the ARIC study, heavy alcohol consumption (>210 g/week or about >3 glasses/d for men, >105 g/week or about >1·5 glasses/d for women) did not have beneficial association with plasma apoB( Reference Volcik, Ballantyne and Fuchs 154 ). Moreover, a J-shaped relationship has been described in regards to plasma TAG, where low-moderate alcohol consumption is associated with lower plasma TAG while heavy alcohol consumption is associated with higher plasma TAG( Reference Klop, do Rego and Cabezas 159 ). A similar relationship may exist in regards to plasma apoB.
Only two studies employed an RCT design to examine the effect of alcohol or grape extract on plasma apoB. In one RCT, daily consumption of red wine (about three glasses), though not dealcoholised red wine, reduced fasting plasma LDL-C and increased HDL-C, but had no effect on plasma apoB in forty-five postmenopausal women( Reference Naissides, Mamo and James 160 ). This is in contrast to in vitro findings where incubation of HepG2 cells( Reference Pal, Ho and Santos 161 ) or Caco-2 intestinal cells( Reference Pal, Ho and Takechi 162 ) with either red wine or dealcoholised red wine, but not ethanol, reduced apoB100 synthesis and apoB48 secretions, respectively. Of note, red wine may provide a greater health benefit compared with other alcoholic beverages due to its high resveratrol content, a polyphenol recognised for its cardioprotective properties. In another RCT, resveratrol-enriched (8 mg) grape extract reduced plasma apoB and oxidised LDL without any effect on plasma TAG or HDL-C in statin-treated patients( Reference Tomé-Carneiro, Gonzálvez and Larrosa 163 ). Finally, the few studies that examined the effect of alcohol on apoA1 (four studies) and apoB:apoA1 (two studies) reported a benefit on these parameters.
Thus, most evidence to date on the association of alcohol consumption with reduced plasma apoB is derived from three out of four cross-sectional population studies (20 547 in total( Reference Volcik, Ballantyne and Fuchs 154 – Reference Simonsson, Schmidt and Sigurdadottir 157 )), while the available RCT on forty-five women reported no effect( Reference Naissides, Mamo and James 160 ). More research employing the RCT design is needed to explore the role of the quantity and the type of alcohol consumed on the regulation of plasma apoB, apoB:apoA1 and other lipoprotein-related parameters in healthy and hyperlipidaemic subjects.
Effects of micronutrients on plasma apoB
In line with their antioxidant properties that combat oxidative stress involved in the pathogenesis of T2D, high dietary intake of vitamins A, C and E and Mg have been associated with lower risk of diabetes( Reference Martini, Catania and Ferreira 164 , Reference Montonen, Knekt and Jarvinen 165 ). Moreover, a protective role for a higher intake of vitamin D on the development of the metabolic syndrome has been reported in association studies( Reference Al-Daghri, Alkharfy and Al-Saleh 166 , Reference McGill, Stewart and Lithander 167 ). However, interventional studies using these micronutrients reported conflicting results( Reference Martini, Catania and Ferreira 164 , Reference Czernichow, Vergnaud and Galan 168 ) and none addressed plasma apoB. Much more research is needed in this area.
Effects of specific foods and healthy dietary patterns on plasma apoB
Studying the effect of healthy food items and dietary patterns is essential and may have a greater benefit on atherogenic apoB-lipoproteins than the individual components described above. This is due to their high complexity, possible nutrient interactions and presence of other non-nutritive bioactive components such as phytochemicals. Moreover, the effects of nutrients that may remain unidentified are also considered.
Specific foods
Nuts contain a high amount of fat of favourable FA composition, which would be expected to reduce plasma apoB. These food items are low in SFA and have almost half of their total fat content in the form of MUFA, except for walnuts that are predominantly composed of PUFA( Reference Ros and Mataix 169 ). Nuts are also rich in fibre, several vitamins and minerals and phytochemicals including phenols (particularly walnuts), phytosterols, proanthocyanidins and carotenoids( Reference Chen and Blumberg 170 ). High intake of such phytochemical-rich foods has been associated with lower risk for abdominal obesity and hypertriacylglycerolaemia( Reference Bahadoran, Golzarand and Mirmiran 171 ).
Three RCT reported that the consumption of mixed nuts (75 g/d or half a portion in 117 T2D subjects)( Reference Jenkins, Kendall and Banach 172 ), walnuts (43 g/d in forty healthy subjects)( Reference Wu, Piotrowski and Rau 173 ) or hazelnuts (30 g/d in forty-six hypercholesterolaemic subjects)( Reference Tey, Brown and Chisholm 174 ) reduces plasma apoB, with no effect on TAG and inconsistent effects on the other lipoprotein parameters. In contrast, one RCT reported no effect of hazelnuts (30 g/d) when added to a cocoa cream alone, and a decrease in plasma apoB100 and LDL-C when combined with phytosterols and soluble fibre( Reference Sola, Valls and Godas 78 ). Of note, these studies used a background diet of 39–45 % CHO, 34–41 % fat, 15–19 % protein, 11–22 % MUFA, 9–12 % SFA and 5–14 % PUFA, which is within the ranges observed to reduce plasma apoB (summarised in the Abstract and Conclusion). More RCT are needed to confirm the effect of nuts on plasma apoB and other lipoprotein parameters.
Higher consumption of soya nuts and products is believed to favour a lower incidence of CVD in the Asian compared with the Western population( Reference Zhang, Shu and Gao 175 – Reference Kokubo, Iso and Ishihara 177 ). However, results are inconsistent in regards to the effects of different soya products on plasma apoB. Consumption of soya nuts instead of equal amounts of non-soya products was reported to reduce plasma apoB and LDL-C in hypertensive, though not normotensive, postmenopausal women( Reference Welty, Lee and Lew 178 ). In contrast, no improvement in plasma apoB was reported in subjects on peritoneal dialysis with the consumption of soya flour that provided more soya proteins and fibres compared with a control meat diet( Reference Tabibi, Imani and Hedayati 179 ). On the other hand, fermented soyabean reduced plasma apoB, though not lipids, in healthy subjects( Reference Back, Kim and Yang 180 ); however, fermentation of isoflavones is known to increase their bioavailability by carrying out their conversion from glycones to bioactive aglycones( Reference Hati, Vij and Singh 181 ).
Studies examining the effects of whole-grain- and legume-rich diets on plasma apoB are scarce and inconsistent. In one RCT in forty-six healthy women, a diet rich in whole-grain barley and legumes reduced plasma apoB and LDL-C in comparison with a diet with equivalent macronutrients and fibres( Reference Tovar, Nilsson and Johansson 182 ). In another study, no effects of mixed whole-grain cereal products on plasma apoB were reported in fifty-four subjects with the metabolic syndrome( Reference Giacco, Costabile and Della Pepa 183 ). However, these specific foods contain prebiotics such as dietary fibre, resistant starch, α-galactosides and β-glucans, as well as polyphenols and phenolic acids, all of which can be used as substrates for colonic fermentation. The subsequent production of SCFA and their influence on lipid metabolism deserve further studies.
Other specific food items explored in regards to their effects on plasma apoB include: partially skimmed 2 % fat milk (3·2 servings/d) in twenty-seven postmenopausal women with abdominal obesity( Reference Drouin-Chartier, Gagnon and Labonte 184 ), buttermilk (45 g/d) in thirty-four subjects with low risk of CVD( Reference Conway, Couture and Richard 185 ), kiwifruit (two per d) in seventy men with hypercholesterolaemia( Reference Gammon, Kruger and Conlon 186 ), raw tomato (200 g/d) in thirty-two men with T2D( Reference Shidfar, Froghifar and Vafa 187 ), and garlic powder (2·4 g/d allicin) in fifty-six subjects with severe coronary artery disease( Reference Mahdavi-Roshan, Zahedmehr and Mohammad-Zadeh 188 ). None of these foods had an effect on plasma apoB, and had only a minor, if any, effect on the other plasma lipoprotein parameters.
Mediterranean diet
The Mediterranean diet (Med diet) captured the interest of many scientists in the early 1960s because of longer life expectancy and lower prevalence of CVD observed in Greece and southern Italy( Reference Willett, Sacks and Trichopoulou 189 ). These populations have a high consumption of fruits, vegetables, cereal products, potatoes, beans, nuts and seeds, use olive oil as the principal source of fat, have frequent intake of fish and sea products, moderate intake of wine, dairy products, poultry and eggs, and low intake of red meat and sweets. This dietary pattern translates into a diet that is moderate in alcohol, CHO and fat content, low in SFA and cholesterol, and high in MUFA, n-3 PUFA and fibre, all of which promote a lower plasma apoB. In addition to its high nutritional quality, a Med diet may reduce plasma apoB as it supports weight loss secondary to its low energy density and high satiety effect.
Of the seven studies examining the effect of a Med diet on plasma apoB, only two employed an RCT design. They reported a decrease in fasting plasma apoB (95 % CI –0·001, –0·056 g/l( Reference Sola, Fito and Estruch 190 )) or postprandial apoB48( Reference Defoort, Vincent-Baudry and Lairon 191 , Reference Vincent-Baudry, Defoort and Gerber 192 ) on 13 weeks of a Med diet (45–46 % CHO, 35 % fat, and 18–20 % protein, 9–10 % SFA, 16–17 % MUFA, 6 % PUFA) in a total of 686 subjects at risk for CVD. A reduction in plasma TAG was also induced with both diets, while insufficient data exist for the other lipoprotein parameters. Notably, the high-MUFA/low-SFA content of the Med diet appears to play a major role. In a controlled parallel trial, a Western-type diet (46 % CHO, 40 % fat, 11 % protein) also reduced plasma apoB, LDL-C and TAG when MUFA intake was increased (11 to 20 %) and that of SFA was reduced (19 to 11 %) in abdominally obese subjects, and to a similar extent as a Med diet (average –0·10 v. –0·15 g/l, respectively)( Reference van Dijk, Feskens and Bos 85 , Reference Bos, de Vries and Feskens 86 ). Results from two prospective intervention studies also support a favourable impact on plasma apoB and LDL-C, independent of weight loss( Reference Bedard, Riverin and Dodin 193 – Reference Richard, Couture and Ooi 195 ), which was attributed to increased LDL-apoB fractional catabolic rate( Reference Richard, Couture and Desroches 194 , Reference Richard, Couture and Ooi 195 ). Similarly, a large cross-sectional study (n 20 986) reported an association between a Med diet score and lower apoB:apoA1 and TAG and higher HDL-C, even after adjustment for BMI and nine other confounders( Reference Sotos-Prieto, Luben and Khaw 196 ). The impact of a hypoenergetic Med diet as a weight-loss intervention is less clear; prospective intervention studies found either a reduction of( Reference Richard, Couture and Desroches 194 , Reference Richard, Couture and Ooi 195 ), or no impact on( Reference Beltaifa, Chaouachi and Zerifi 197 ), plasma apoB. However, the first population was in nineteen men with the metabolic syndrome( Reference Richard, Couture and Desroches 194 , Reference Richard, Couture and Ooi 195 ), while the other was in twenty-six healthy women( Reference Beltaifa, Chaouachi and Zerifi 197 ). Thus the heterogeneity and small sample size of the populations examined probably affected the outcomes.
In summary, two RCT and three intervention studies reported the reduction in plasma apoB, LDL-C and TAG using a Med dietary pattern (41–50 % CHO, 32–40 % fat, 15–20 % protein, 16–21 % MUFA, 7–11 % SFA, 5–7 % PUFA) over 4–13 weeks in a total of 823 subjects, the majority of whom (>94 %) were at risk for CVD( Reference van Dijk, Feskens and Bos 85 , Reference Bos, de Vries and Feskens 86 , Reference Sola, Fito and Estruch 190 – Reference Richard, Couture and Ooi 195 ). Of note, the composition of these Med diets used fits within the macronutrient ranges observed to reduce plasma apoB (summarised in the Abstract and Conclusion). Furthermore, a large cross-sectional study also reported that higher adherence to a Med diet is associated with lower plasma apoB:apoA1 and TAG and higher HDL-C in 20 986 British subjects. More RCT are needed to confirm the beneficial effect of a weight-maintenance or a hypoenergetic Med diet on plasma apoB, apoB:apoA1 in comparison with other lipoprotein parameters in healthy and hyperlipidaemic subjects.
Vegetarian diet
Vegetarian diets are associated with lower plasma cholesterol and prevalence of CVD and T2D( Reference Zhang, Han and Sun 198 ). Vegetarian diets exclude meat, poultry and/or fish, while vegan diets exclude all animal products, resulting in lower SFA and cholesterol and higher MUFA, PUFA and fibre intake, which is expected to reduce plasma apoB. While this hypothesis is yet to be proven by RCT, three cross-sectional studies on vegetarian/vegan diets reported lower plasma apoB in Europeans (n 1694)( Reference Bradbury, Crowe and Appleby 199 ) and Buddhist monks (men) (n 296)( Reference Zhang, Han and Sun 198 ), even after adjustment for confounders such as BMI, while adjustment for BMI in sixty-two women eliminates their significance( Reference Karelis, Fex and Filion 200 ). Vegetarian diets were also associated with lower HDL-C and apoA1 after adjustment for many confounders, probably secondary to their higher CHO content compared with the omnivorous control diets in these studies( Reference Zhang, Han and Sun 198 , Reference Bradbury, Crowe and Appleby 199 ). They were also associated with lower apoB:apoA1 in men( Reference Karelis, Fex and Filion 200 ), while their association with lower apoB:apoA1 in women was eliminated after adjustment for BMI( Reference Karelis, Fex and Filion 200 ). These findings need to be confirmed by RCT.
Moreover, indole-3-carbinol, which is produced from the breakdown of the glucosinolate glucobrassicin found at relatively high levels in cruciferous vegetables such as broccoli, cabbage, and cauliflower was reported to reduce apoB production in HepG2 cells( Reference Maiyoh, Kuh and Casaschi 201 ). Human studies are lacking and the role of the vegetarian diet and its components needs to be explored.
Nordic diet
Consumption of traditional Nordic foods has been associated with lower total mortality( Reference Olsen, Egeberg and Halkjaer 202 ). Though limited, two recent RCT using Nordic diets that mainly included higher intake of whole-grain products, berries, fruits, vegetables, rapeseed oil, fish and low-fat dairy products, and lower intake of sugar-sweetened products, reported a reduction in either plasma apoB (95 % CI –0·19, –0·31 g/l)( Reference Adamsson, Reumark and Fredriksson 203 ) or apoB:apoA1 ratio (95 % CI –0·01, –0·11 g/l)( Reference Adamsson, Reumark and Fredriksson 203 , Reference Uusitupa, Hermansen and Savolainen 204 ) in subjects with hypercholesterolaemia or the metabolic syndrome. A less consistent effect was observed for LDL-C, HDL-C and apoA1, while no effect was reported for plasma TAG. The beneficial effects of Nordic diets may be attributed to higher intakes of fibre and PUFA and a lower intake of SFA( Reference Adamsson, Reumark and Fredriksson 203 , Reference Uusitupa, Hermansen and Savolainen 204 ). Other dietary benefits include increased micronutrient intake (β-carotene, vitamin C, vitamin E, K, Mg) and/or decreased cholesterol and Na intake; although the specific effects of these nutrients on plasma apoB remain unclear. More RCT are needed to explore the effects of a Nordic diet on weight loss or maintenance in various populations.
Dietary Approaches to Stop Hypertension diet
The Dietary Approaches to Stop Hypertension (DASH) encourage higher intake of fruit and vegetables, whole-grain cereals, low-fat dairy products and nuts, and lower intake of salt, refined CHO and SFA. Two trials, one of which was a RCT, reported that a DASH diet led to a reduction in plasma apoB with variable effects on plasma lipids( Reference Valente, Sheehy and Avila 45 , Reference Hodson, Harnden and Roberts 205 ). However, the impact of reduced Na intake per se on plasma apoB is rarely explored. One study that examined this reported no effect of a 7 d low-Na diet on plasma apoB, LDL-C and TAG with a decrease in HDL-C in normotensive men( Reference Krikken, Dallinga-Thie and Navis 206 ). More RCT are also needed exploring the effects of a DASH diet on plasma apoB.
Palaeolithic diet
During the Palaeolithic period, our ancestors lived as hunter–gatherers, eating wild animal-source foods (lean meats, fish, eggs, no dairy) and uncultivated plant-source foods (fruits, vegetables, nuts, no cereal grains and legumes)( Reference Frassetto, Schloetter and Mietus-Synder 207 ). This period was followed by agriculture (predominantly of cereals) and animal domestication and more recently, by the industrial revolution (refined fats and sugar, added salt), which introduced major dietary changes. One hypothesis states that time was insufficient for evolutionary adaptation and that a Palaeolithic diet would optimise our metabolism and reduce risk of contemporary chronic diseases. The only study that examined this hypothesis only included ten women with a short duration (5 weeks), not allowing any solid conclusion. Nevertheless, this study reported a reduction in plasma apoB, LDL-C, TAG, HDL-C, together with weight loss, in ten postmenopausal women following an ad libitum Palaeolithic diet( Reference Ryberg, Sandberg and Mellberg 208 ), which may be related to the high MUFA and PUFA and low CHO and SFA content of this diet. More RCT are needed exploring the effects of a Palaeolithic diet in comparison with a Western diet or healthy dietary patterns on plasma apoB and other lipoprotein parameters in various populations.
Conclusion
We analysed eighty-seven recent original studies published within the past 10 years on the concomitant modulation of plasma apoB and other lipoprotein parameters by nutritional components and dietary patterns. When an effect of a dietary component or pattern was reported by the majority of ≥3 interventional studies, the effect was indicated as significant in Table 2. Effects derived from association studies were also highlighted.
Consistent data from seven studies, three of which were RCT, in a total of 335 overweight and obese healthy or hyperlipidaemic subjects indicated that plasma apoB was reduced with hypoenergetic diet-induced weight loss of 6 to 12 %, using diets composed of 5440–7110 kJ (1300–1700 kcal/d), 34–50 % CHO, 27–39 % fat, and 18–24 % protein( Reference Chan, Watts and Gan 41 – Reference Pelletier-Beaumont, Arsenault and Almeras 47 ). Eleven interventional studies, eight of which were RCT, compared macronutrients in isoenergetic diets in a total of 1189 healthy or hyperlipidaemic subjects. These were the studies that compared the effects of different amounts of CHO (see the Carbohydrates section( Reference Shin, Blanche and Rawlings 56 , Reference Krauss, Blanche and Rawlings 59 – Reference Mercanligil, Arslan and Alasalvar 63 )) or replacing SFA by MUFA (see the MUFA and PUFA v. SFA section( Reference Mangravite, Chiu and Wojnoonski 62 , Reference Jebb, Lovegrove and Griffin 82 – Reference Bos, de Vries and Feskens 86 )). The diets that reduced plasma apoB over 3–24 weeks were composed of 26–51 % CHO, 26–46 % fat, 11–32 % protein, 10–27 % MUFA, 5–14 % PUFA and 7–13 % SFA. Notably, among these diets, those that used higher CHO also used higher MUFA and/or lower SFA; thus it is not clear which of these macronutrients has the largest effect on plasma apoB. Nevertheless, replacement of CHO in high- or moderate-CHO diet by MUFA, not SFA, decreased plasma apoB. Few studies were found comparing the effect of MUFA v. PUFA on plasma apoB; however, this may be due to the recent meta-analysis reporting the lack of difference between these two types of unsaturated FA( Reference Mozaffarian and Clarke 81 ).
Five studies, including four RCT, reported that the intake of marine-source n-3 FA from natural fish sources (1·1–1·7 g/d) or supplementation (3·2–3·4 g/d, EPA:DHA, 1·2:1 or 4 g/d EPA alone) decreased plasma apoB( Reference Bays, Ballantyne and Kastelein 98 , Reference Zhang, Wang and Li 101 , Reference Wong, Chan and Ooi 103 – Reference Ooi, Lichtenstein and Millar 105 ). This was examined mostly in hyperlipidaemic subjects (n 411). Additional effects of n-3 FA (3·4 g/l) on plasma apoB was reported with simvastatin( Reference Davidson, Stein and Bays 99 ), but not with atorvastatin( Reference Bays, McKenney and Maki 100 ). While fewer RCT exist (three or four per component), they indicate that enriching the diet with soluble fibre such as psyllium (about 8–20 g/d)( Reference Shrestha, Volek and Udani 76 – Reference Comerford, Artiss and Jen 79 ), phytosterols (about 2–4 g/d)( Reference Shrestha, Volek and Udani 76 , Reference Sola, Valls and Godas 78 , Reference Sialvera, Pounis and Koutelidakis 133 ) or nuts (30–75 g/d)( Reference Jenkins, Kendall and Banach 172 – Reference Tey, Brown and Chisholm 174 ) decreases plasma apoB (examined only in hyperlipidaemic subjects for psyllium and phytosterol). A high intake of trans-FA (4·3–9·1 %)( Reference Vega-López, Matthan and Ausman 115 , Reference Wanders, Brouwer and Siebelink 116 ) has been reported to increase plasma apoB. However, with the worldwide recommendation to reduce trans-FA intake to <1 %, it is unlikely that these elevated doses represent usual consumption. While inconsistent data were found in eight RCT regarding the replacement of milk proteins with soya proteins (25–30 g/d)( Reference Campbell, Khalil and Payton 138 – Reference Kwak, Ahn and Park 147 ), the effect of soya protein may be specific to patients with hyperlipidaemia. Differential regulation of plasma apoB and TAG v. non-HDL-C, LDL-C and VLDL-C by weight loss, moderate CHO and high n-3 FA intake was noted, as these appear to benefit plasma apoB and TAG only.
Solid evidence from five studies( Reference van Dijk, Feskens and Bos 85 , Reference Bos, de Vries and Feskens 86 , Reference Sola, Fito and Estruch 190 – Reference Richard, Couture and Ooi 195 ), including two RCT( Reference Sola, Fito and Estruch 190 – Reference Vincent-Baudry, Defoort and Gerber 192 ), in a total of 823 subjects mostly at risk for CVD indicates that following an isoenergetic Med diet decreases plasma apoB, LDL-C and TAG. Cross-sectional studies suggest that alcohol consumption( Reference Volcik, Ballantyne and Fuchs 154 – Reference Simonsson, Schmidt and Sigurdadottir 157 ) and vegetarian diets( Reference Zhang, Han and Sun 198 – Reference Karelis, Fex and Filion 200 ) are associated with lower plasma apoB in 20 547 and 2052 subjects, respectively. However, RCT are lacking to confirm these observations and clarify the quantities and types of alcohol with the biggest effect of plasma apoB. Few other studies examined the regulation of the plasma apoB:apoA1 ratio; thus findings were insufficient. No effect or insufficient data were found using specific dietary components (MCFA as oil or in dietary items, fructose v. glucose, α-cyclodextrin v. psyllium fibre, plant-derived PUFA α-linolenic acid, whey or cowpea protein), dietary patterns (DASH, Nordic or Palaeolithic diet), food items (soya products, barley, legumes, whole grains, buttermilk, milk fat, kiwifruit, tomato, garlic powder) and vitamins and minerals. Future RCT need to explore the effects of these dietary components and patterns on plasma apoB and apoB:apoA1, and confirm the beneficial roles of soya protein, moderate alcohol intake, and vegetarian diets in healthy and hyperlipidaemic subjects during weight-loss or weight-maintenance interventions.
In summary, the healthy dietary pattern with the strongest reported evidence to reduce plasma apoB is a Mediterranean diet. This is probably because it encompasses the overall macronutrient composition (moderate CHO and fat, high n-3 FA, MUFA and PUFA, low SFA, and moderate alcohol) and dietary components (high psyllium, phytosterols and nuts) individually observed to reduce plasma apoB in the present review. It is this overall dietary pattern of a Mediterranean diet, rather than its individual components, that needs to be encouraged for optimal nutritional management of hyperapoB and for reducing the risk of CVD and T2D in humans.
Acknowledgements
The present review is supported by an operating grant from the Canadian Institute of Health Research (CIHR, MOP# 93581) to M. F.; M. F. is the recipient of salary support from the CIHR and Fonds de recherche du Québec (FRQ); V. L. is the recipient of a Vanier Canada Graduate Scholarship.
V. L. and M. F. conducted the literature review and manuscript writing; A. S. and M. F. reviewed and edited the manuscript. All authors read and approved the final manuscript.
There are no conflicts of interest.
