Hostname: page-component-848d4c4894-cjp7w Total loading time: 0 Render date: 2024-06-20T00:14:27.687Z Has data issue: false hasContentIssue false

PTEN influences insulin and lipid metabolism in bovine hepatocytes in vitro

Published online by Cambridge University Press:  01 March 2019

Qinghua Deng
College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, China
Dehui Ma
College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, China
Guoquan Sun
College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, China
Xue Yuan
College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, China
Zhe Wang
College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin, 130062, China
Guowen Liu*
College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, China College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin, 130062, China
Author for correspondence: Guowen Liu, Email:


Dairy cows with fatty liver or ketosis display decreased insulin sensitivity and defects in the insulin receptor substrate (IRS)/PI3K/AKT signaling pathway. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor and also a negative regulator of insulin signaling and peripheral insulin sensitivity. We investigated the hypothesis that PTEN may affect the insulin pathway-mediated hepatic glucose and lipid metabolism in dairy cows. Adenovirus vectors that over-express and silence PTEN were constructed, and then transfected into hepatocytes isolated from calves to investigate the effect of PTEN on PI3K/AKT signaling pathway. PTEN silencing increased the phosphorylation of AKT and the expression of PI3K but decreased the phosphorylation of IRS1, which increased the phosphorylation levels of glycogen synthase kinase-3β (GSK-3β) and expression of sterol regulatory element-binding protein-1c (SREBP-1c). Increased GSK-3β phosphorylation further up-regulated expression of the key enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6-Pase) involved in gluconeogenesis. Furthermore, the expression of SREBP-1c target gene fatty acid synthase (FAS) also increased significantly. We further showed that PTEN over-expression could reverse the above results. PTEN negatively regulates the enzymes involved in hepatic gluconeogenesis and lipid synthesis, which suggests that PTEN may be a therapeutic target for ketosis and fatty liver in dairy cows.

Research Article
Copyright © Hannah Dairy Research Foundation 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Chen, CY, Chen, J, He, L and Stiles, BL (2018) PTEN: tumor suppressor and metabolic regulator. Frontiers in Endocrinology 9, 338.Google Scholar
Deng, Q, Li, X, Fu, S, Yin, L, Zhang, Y, Wang, T, Wang, J, Liu, L, Yuan, X, Sun, G, Wang, Z, Liu, G and Li, X (2014) SREBP-1c gene silencing can decrease lipid deposits in bovine hepatocytes cultured in vitro. Cellular Physiology and Biochemistry 33, 15681578.Google Scholar
Fu, S, Deng, Q, Yang, W, Ding, H, Wang, X, Li, P, Li, X, Wang, Z, Li, X and Liu, G (2012) Increase of fatty acid oxidation and VLDL assembly and secretion overexpression of PTEN in cultured hepatocytes of newborn calf. Cellular Physiology and Biochemistry 30, 10051013.Google Scholar
Gao, Y, Su, P, Wang, C, Zhu, K, Chen, X, Liu, S and He, J (2013) The role of PTEN in chronic growth hormone-induced hepatic insulin resistance. PLoS ONE 8, e68105.Google Scholar
Horie, Y, Suzuki, A, Kataoka, E, Sasaki, T, Hamada, K, Sasaki, J, Mizuno, K, Hasegawa, G, Kishimoto, H, Iizuka, M, Naito, M, Enomoto, K, Watanabe, S, Mak, TW and Nakano, T (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. Journal of Clinical Investigation 113, 17741783.Google Scholar
Itle, AJ, Huzzey, JM, Weary, DM and von Keyserlingk, MA (2015) Clinical ketosis and standing behavior in transition cows. Journal of Dairy Science 98, 128134.Google Scholar
Jayakumar, R, Lanjewar, S and Axiotis, CA (2018) Loss of PTEN and increased pAKT expression distinguishes aggressive low-grade neuroendocrine tumors. Annals of Clinical and Laboratory Science 48, 565572.Google Scholar
Jia, J, Zhan, D, Li, J, Li, Z, Li, H and Qian, J (2018) The contrary functions of lncRNA HOTAIR/miR-17-5p/PTEN axis and Shenqifuzheng injection on chemosensitivity of gastric cancer cells. Journal of Cellular and Molecular Medicine 23, 656669.Google Scholar
Kuo, YH, Lin, CH and Shih, CC (2014) Caffeamide 36-13 regulates the antidiabetic and hypolipidemic signs of high-fat-fed mice on glucose transporter 4, AMPK phosphorylation, and regulated hepatic glucose production. Evidence Based Complementary and Alternative Medicine 2014, 821569.Google Scholar
LeBlanc, S (2010) Monitoring metabolic health of dairy cattle in the transition period. Journal of Reproduction and Development 56(suppl), S29S35.Google Scholar
Li, Y, Ding, H, Wang, X, Liu, L, Huang, D, Zhang, R, Guo, L, Wang, Z, Li, X, Liu, G, Wu, J and Li, X (2016) High levels of acetoacetate and glucose increase expression of cytokines in bovine hepatocytes, through activation of the NF-kappaB signalling pathway. Journal of Dairy Research 83, 5157.Google Scholar
Li, X, Li, Y, Ding, H, Dong, J, Zhang, R, Huang, D, Lei, L, Wang, Z, Liu, G and Li, X (2018) Insulin suppresses the AMPK signaling pathway to regulate lipid metabolism in primary cultured hepatocytes of dairy cows. Journal of Dairy Research 85, 157162.Google Scholar
Mann, S, Leal Yepes, FA, Duplessis, M, Wakshlag, JJ, Overton, TR, Cummings, BP and Nydam, DV (2016) Dry period plane of energy: effects on glucose tolerance in transition dairy cows. Journal of Dairy Science 99, 701717.Google Scholar
Nakamura, A, Tajima, K, Zolzaya, K, Sato, K, Inoue, R, Yoneda, M, Fujita, K, Nozaki, Y, Kubota, KC, Haga, H, Kubota, N, Nagashima, Y, Nakajima, A, Maeda, S, Kadowaki, T and Terauchi, Y (2012) Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. Diabetologia 55, 33823391.Google Scholar
Peyrou, M, Bourgoin, L and Foti, M (2010) PTEN in liver diseases and cancer. World Journal of Gastroenterology 16, 46274633.Google Scholar
Peyrou, M, Bourgoin, L, Poher, AL, Altirriba, J, Maeder, C, Caillon, A, Fournier, M, Montet, X, Rohner-Jeanrenaud, F and Foti, M (2015) Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice. Journal of Hepatology 62, 421429.Google Scholar
Raboisson, D, Mounie, M and Maigne, E (2014) Diseases, reproductive performance, and changes in milk production associated with subclinical ketosis in dairy cows: a meta-analysis and review. Journal of Dairy Science 97, 75477563.Google Scholar
Rayasam, GV, Tulasi, VK, Sodhi, R, Davis, JA and Ray, A (2009) Glycogen synthase kinase 3: more than a namesake. British Journal of Pharmacology 156, 885898.Google Scholar
Saltiel, AR and Kahn, CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799806.Google Scholar
Tappy, L and Le, KA (2010) Metabolic effects of fructose and the worldwide increase in obesity. Physiological Reviews 90, 2346.Google Scholar
Terauchi, Y, Tsuji, Y, Satoh, S, Minoura, H, Murakami, K, Okuno, A, Inukai, K, Asano, T, Kaburagi, Y, Ueki, K, Nakajima, H, Hanafusa, T, Matsuzawa, Y, Sekihara, H, Yin, Y, Barrett, JC, Oda, H, Ishikawa, T, Akanuma, Y, Komuro, I, Suzuki, M, Yamamura, K, Kodama, T, Suzuki, H, Yamamura, K, Kodama, T, Suzuki, H, Koyasu, S, Aizawa, S, Tobe, K, Fukui, Y, Yazaki, Y and Kadowaki, T (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nature Genetics 21, 230235.Google Scholar
Uchimura, K, Hayata, M, Mizumoto, T, Miyasato, Y, Kakizoe, Y, Morinaga, J, Onoue, T, Yamazoe, R, Ueda, M, Adachi, M, Miyoshi, T, Shiraishi, N, Ogawa, W, Fukuda, K, Kondo, T, Matsumura, T, Araki, E, Tomita, K and Kitamura, K (2014) The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling. Nature Communications 5, 3428.Google Scholar
Ueki, K, Yballe, CM, Brachmann, SM, Vicent, D, Watt, JM, Kahn, CR and Cantley, LC (2002) Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proceedings of the National Academy of Sciences of the U S A 99, 419424.Google Scholar
Wang, Z, Hou, X, Qu, B, Wang, J, Gao, X and Li, Q (2014) Pten regulates development and lactation in the mammary glands of dairy cows. PLoS ONE 9, e102118.Google Scholar
Wang, Q, Sun, X, Li, X, Dong, X, Li, P and Zhao, L (2015) Resveratrol attenuates intermittent hypoxia-induced insulin resistance in rats: involvement of Sirtuin 1 and the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway. Molecular Medicine Reports 11, 151158.Google Scholar
Worby, CA and Dixon, JE (2014) PTEN. Annual Reviews of Biochemistry 83, 641669.Google Scholar
Zhang, ZG, Li, XB, Gao, L, Liu, GW, Kong, T, Li, YF, Wang, HB, Zhang, C, Wang, Z and Zhang, RH (2012) An updated method for the isolation and culture of primary calf hepatocytes. Veterinary Journal 191, 323326.Google Scholar
Supplementary material: PDF

Deng et al. supplementary material

Deng et al. supplementary material 1

Download Deng et al. supplementary material(PDF)
PDF 197.9 KB