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PTEN influences insulin and lipid metabolism in bovine hepatocytes in vitro

  • Qinghua Deng (a1), Dehui Ma (a1), Guoquan Sun (a1), Xue Yuan (a1), Zhe Wang (a2) and Guowen Liu (a1) (a2)...

Abstract

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.

Copyright

Corresponding author

Author for correspondence: Guowen Liu, Email: liuguowen2008@163.com

References

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Chen, CY, Chen, J, He, L and Stiles, BL (2018) PTEN: tumor suppressor and metabolic regulator. Frontiers in Endocrinology 9, 338.
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.
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.
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.
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.
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.
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.
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.
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.
LeBlanc, S (2010) Monitoring metabolic health of dairy cattle in the transition period. Journal of Reproduction and Development 56(suppl), S29S35.
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.
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.
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.
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.
Peyrou, M, Bourgoin, L and Foti, M (2010) PTEN in liver diseases and cancer. World Journal of Gastroenterology 16, 46274633.
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.
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.
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.
Saltiel, AR and Kahn, CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799806.
Tappy, L and Le, KA (2010) Metabolic effects of fructose and the worldwide increase in obesity. Physiological Reviews 90, 2346.
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.
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.
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.
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.
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.
Worby, CA and Dixon, JE (2014) PTEN. Annual Reviews of Biochemistry 83, 641669.
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.
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Journal of Dairy Research
  • ISSN: 0022-0299
  • EISSN: 1469-7629
  • URL: /core/journals/journal-of-dairy-research
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