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Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Published online by Cambridge University Press:  09 March 2016

D. D. Liu ,
C. C. Han ,
H. F. Wan ,
F. He ,
H. Y. Xu ,
S. H. Wei ,
X. H. Du  and
F. Xu
D. D. Liu
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
C. C. Han*
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
H. F. Wan
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
F. He
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
H. Y. Xu
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
S. H. Wei
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
X. H. Du
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
F. Xu
Affiliation:
Institute of Animal Breeding & Genetics, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China
*
†E-mail: [email protected]
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Abstract

Phosphatidylinositol-3 kinases (PI3K)-Protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway plays an important role in the synthesis and secretion of triacylglycerol. However, the mechanism of PI3K-Akt-mTOR pathway in regulating lipid metabolism of goose liver was poorly understood. The purpose of this study was to determine how PI3K-Akt-mTOR pathway regulating lipid metabolic homeostasis in goose hepatocytes. Goose primary hepatocytes were treated with different PI3K-Akt-mTOR signal inhibitors (LY294002, rapamycin and NVP-BEZ235) for 24 h. The results showed that these inhibitors evidently inhibited PI3K-Akt-mTOR downstream signaling. Meanwhile, these PI3K-Akt-mTOR inhibitors reduced intracellular lipid accumulation, decreased the mRNA expression and protein content of genes involved in the de novo fatty acid synthesis, while increased the transcriptional and protein level of key factors involved in fatty acid oxidation and very low density lipoprotein (VLDL) assembly and secretion. Conclusion: These findings suggested that the reduction of lipids accumulation induced-by inhibiting PI3K-Akt-mTOR pathway was closely linked to the decrease of lipogenesis, the increase of fatty acids oxidation, and the increase of VLDL assembly and secretion in goose hepatocytes.

Keywords

PI3K-Akt-mTOR pathwaylipids metabolismgoose hepatocyte
Type
Research Article
Information
animal , Volume 10 , Issue 8 , August 2016 , pp. 1319 - 1327
Copyright
© The Animal Consortium 2016 

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References

Brown, NF, Stefanovic-Racic, M, Sipula, IJ and Perdomo, G 2007. The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metabolism 56, 1500–1507.Google Scholar
Denechaud, PD, Bossard, P, Lobaccaro, JM, Millatt, L, Staels, B, Girard, J and Postic, C 2008. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. The Journal of Clinical Investigation 118, 956–964.Google Scholar
Dentin, R, Benhamed, F, Hainault, I, Fauveau, V, Foufelle, F, Dyck, JR, Girard, J and Postic, C 2006. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55, 2159–2170.CrossRefGoogle ScholarPubMed
Evert, M, Calvisi, DF, Evert, K, De Murtas, V, Gasparetti, G, Mattu, S, Destefanis, G, Ladu, S, Zimmermann, A and Delogu, S 2012. V‐AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin activation induces a module of metabolic changes contributing to growth in insulin‐induced hepatocarcinogenesis. Hepatology 55, 1473–1484.Google Scholar
Fingar, DC, Richardson, CJ, Tee, AR, Cheatham, L, Tsou, C and Blenis, J 2004. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Molecular and Cellular Biology 24, 200–216.Google Scholar
Han, CC, Wang, J, Li, L, Wang, L and Zhang, Z 2009. The role of LXRα in goose primary hepatocyte lipogenesis. Molecular and Cellular Biochemistry 322, 37–42.Google Scholar
Han, CC, Wang, J, Xu, H, Li, L, Ye, J, Jiang, L and Zhuo, W 2008. Effect of overfeeding on plasma parameters and mRNA expression of genes associated with hepatic lipogenesis in geese. Asian Australasian. Journal of Animal Sciences 21, 590–595.Google Scholar
Hao, J, Liu, S, Zhao, S, Liu, Q, Lv, X, Chen, H, Niu, Y and Duan, H 2011. PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-β1. Histochemistry and Cell Biology 135, 173–181.Google Scholar
Hao, J, Zhu, L, Li, F, Liu, Q, Zhao, X, Liu, S, Xing, L, Feng, X and Duan, H 2013. Phospho-mTOR: a novel target in regulation of renal lipid metabolism abnormality of diabetes. Experimental Cell Research 319, 2296–2306.Google Scholar
Jeon, TI and Osborne, TF 2012. SREBPs: metabolic integrators in physiology and metabolism. Trends in Endocrinology and Metabolism 23, 65–72.Google Scholar
Kamagate, A and Dong, HH 2008a. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle 7, 3162–3170.Google Scholar
Kamagate, A, Qu, S, Perdomo, G, Su, D, Kim, DH, Slusher, S, Meseck, M and Dong, HH 2008b. FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. The Journal of Clinical Investigation 118, 2347–2364.Google Scholar
Krycer, JR, Sharpe, LJ, Luu, W and Brown, AJ 2010. The Akt–SREBP nexus: cell signaling meets lipid metabolism. Trends in Endocrinology and Metabolism 21, 268–276.CrossRefGoogle ScholarPubMed
Laplante, M and Sabatini, DM 2010. mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proceedings of the National Academy of Sciences 107, 3281–3282.Google Scholar
Liao, W, Hui, TY, Young, SG and Davis, RA 2003. Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER. Journal of Lipid Research 44, 978–985.Google Scholar
Mascaró, C, Acosta, E, Ortiz, JA, Marrero, PF, Hegardt, FG and Haro, D 1998. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. Journal of Biological Chemistry 273, 8560–8563.Google Scholar
Monsalve, FA, Pyarasani, RD, Delgado-Lopez, F and Moore-Carrasco, R 2013. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators of Inflammation 2013, 287–288.Google Scholar
Mori, M, Itabe, H, Higashi, Y, Fujimoto, Y, Shiomi, M, Yoshizumi, M, Ouchi, Y and Takano, T 2001. Foam cell formation containing lipid droplets enriched with free cholesterol by hyperlipidemic serum. Journal of Lipid Research 42, 1771–1781.CrossRefGoogle ScholarPubMed
Natali, F, Siculella, L, Salvati, S and Gnoni, GV 2007. Oleic acid is a potent inhibitor of fatty acid and cholesterol synthesis in C6 glioma cells. Journal of Lipid Research 48, 1966–1975.Google Scholar
Nguyen, P, Leray, V, Diez, M, Serisier, S, Bloc’h, JL, Siliart, B and Dumon, H 2008. Liver lipid metabolism. Journal of Animal Physiology and Animal Nutrition 92, 272–283.Google Scholar
Osaki, M, Oshimura, Ma and Ito, H 2004. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9, 667–676.Google Scholar
Parent, R, Kolippakkam, D, Booth, G and Beretta, L 2007. Mammalian target of rapamycin activation impairs hepatocytic differentiation and targets genes moderating lipid homeostasis and hepatocellular growth. Cancer Research 67, 4337–4345.CrossRefGoogle ScholarPubMed
Reddy, JK and Hashimoto, T 2001. Peroxisomal β-oxidation and peroxisome proliferator-activated receptor α: an adaptive metabolic system. Annual Review of Nutrition 21, 193–230.Google Scholar
Seglen, PO 1976. Preparation of isolated rat liver cells. Methods in Cell Biology 13, 29–83.Google Scholar
Sidiropoulos, KG, Meshkani, R, Avramoglu-Kohen, R and Adeli, K 2007. Insulin inhibition of apolipoprotein B mRNA translation is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve internal ribosomal entry site (IRES) initiation. Archives of Biochemistry and Biophysics 465, 380–388.Google Scholar
Sipula, IJ, Brown, NF and Perdomo, G 2006. Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metabolism 55, 1637–1644.Google Scholar
Soliman, GA 2011. The integral role of mTOR in lipid metabolism. Cell Cycle 10, 861–862.CrossRefGoogle ScholarPubMed
Strable, MS and Ntambi, JM 2010. Genetic control of de novo lipogenesis: role in diet-induced obesity. Critical Reviews in Biochemistry and Molecular Biology 45, 199–214.Google Scholar
Taghibiglou, C, Rashid-Kolvear, F, Van Iderstine, SC, Le-Tien, H, Fantus, IG, Lewis, GF and Adeli, K 2002. Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance. Journal of Biological Chemistry 277, 793–803.Google Scholar
Tobin, KAR, Ulven, SM, Schuster, GU, Steineger, HH, Andresen, SM, Gustafsson, J-Å and Nebb, HI 2002. Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. Journal of Biological Chemistry 277, 10691–10697.Google Scholar
Vara, JÁF, Casado, E, de Castro, J, Cejas, P, Belda-Iniesta, C and González-Barón, M 2004. PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews 30, 193–204.Google Scholar
Wang, X and Proud, CG 2006. The mTOR pathway in the control of protein synthesis. Physiology 21, 362–369.CrossRefGoogle ScholarPubMed
Yoshikawa, T, Shimano, H, Amemiya-Kudo, M, Yahagi, N, Hasty, AH, Matsuzaka, T, Okazaki, H, Tamura, Y, Iizuka, Y and Ohashi, K 2001. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Molecular and Cellular Biology 21, 2991–3000.Google Scholar