Abstract
Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) has markedly increased. Insulin resistance has been implicated in the pathogenesis of NAFLD. This study was aimed at observing the relationship between insulin resistance and NAFLD, and evaluating the role of pioglitazone (PGZ) acting as insulin-sensitizing agents in the prevention and treatment of rat fatty liver induced by high fat feeding. Methods: The rats were separated randomly into 6 groups: model group I were fed high fat diet for 8 weeks, PGZ prevention group were given PGZ 4 mg/(kg·d) simultaneously, while control group I were fed normal food for 8 weeks; model group II were fed high fat diet for 16 weeks, PGZ treatment group were given PGZ 4 mg/(kg·d) orally simultaneous with high fat diet for 8 weeks after high fat feeding for 8 weeks, control group II were fed normal food for 16 weeks. The rats were sacrificed after 8 weeks and 16 weeks respectively. Liver weight, body weight, serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), tumor necrosis factor alpha (TNF-α), fasting blood glucose (FBG), fasting plasma insulin (FINS), HOMA (homeostasis model assessment) insulin resistance index (HOMA-IR), and the liver histology of rats of all groups were assayed. Results: After 8 weeks, the liver in model group I showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration, liver indexes and serum levels of ALT, AST, ALP, TNF-α were significantly increased (P<0.05) compared with control group I. Whereas, the degree of hepatic injury was attenuated in PGZ prevention group, liver indexes and serum levels of ALT, ALP were significantly decreased (P<0.05) compared with model group I. After 16 weeks, notable steatosis, and lobular inflammation were observed in model group II rat liver, while the degree of hepatic injury was attenuated in the PGZ treatment group. Liver index, serum levels of ALT, AST, ALP, FINS and HOMA-IR were significantly increased (P<0.05) in model group II compared with control group II. Whereas, in PGZ treatment group, serum levels of AST and FINS showed decreasing tendency, liver indexes, serum levels of ALT, ALP, TNF-α and HOMA-IR were significantly decreased compared with model group II. Conclusion: Insulin resistance plays a role in the pathogenesis of NAFLD in rats. Pioglitazone can attenuate insulin resistance and biochemical and histological injury in high fat-induced fatty liver in rats.
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References
Bonora, E., Targher, G., Alberiche, M., Bonadonna, R.C., Saggiani, F., Zenere, M.B., Monauni, T., Muggeo, M., 2000. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care, 23(1):57–63.
Bugianesi, E., Leone, N., Vanni, E., Marchesini, G., Brunello, F., Carucci, P., Musso, A., de Paolis, P., Capussotti, L., Salizzoni, M., Rizzetto, M., 2002. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology, 123(1):134–140. [doi:10.1053/gast.2002.34168]
Bugianesi, E., Marzocchi, R., Villanova, N., Marchesini, G., 2004. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): treatment. Best Pract. Res. Clin. Gastroenterol., 18(6):1105–1116. [doi:10.1016/j.bpg.2004.06.025]
Bugianesi, E., McCullough, A.J., Marchesini, G., 2005. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology, 42(5):987–1000. [doi:10.1002/hep.20920]
Clark, J.M., 2006. Weight loss as a treatment for nonalcoholic fatty liver disease. J. Clin. Gastroenterol., 40(Suppl. 1):S39–S43.
Diehl, A.M., 2004. Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin. Liver Dis., 8(3):619–638. [doi:10.1016/j.cld.2004.04.012]
Dixon, J.B., Bhathal, P.S., Hughes, N.R., O’Brien, P.E., 2004. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology, 39(6): 1647–1654. [doi:10.1002/hep.20251]
Galli, A., Crabb, D.W., Ceni, E., Salzano, R., Mello, T., Svegliati-Baroni, G., Ridolfi, F., Trozzi, L., Surrenti, C., Casini, A., 2002. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology, 122(7):1924–1940. [doi:10.1053/gast.2002.33666]
Hauner, H., 2002. The mode of action of thiazolidinediones. Diabetes Metab. Res. Rev., 18(Suppl. 2):S10–S15. [doi:10.1002/dmrr.249]
Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., White, M.F., Spiegelman, B.M., 1996. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance. Science, 271(5249):665–668.
Kon, K., Ikejima, K., Hirose, M., Yoshikawa, M., Enomoto, N., Kitamura, T., Takei, Y., Sato, N., 2002. Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem. Biophys. Res. Commun., 291(1):55–61. [doi:10.1006/bbrc.2002.6385]
Lu, L.G., Zeng, M.D., 2003. The role of improving insulin-resistant in the treatment and prevention of nonalcoholic fatty liver disease. Chin. J. Hepatol., 11(2):113 (in Chinese).
Machado, M., Cortez-Pinto, H., 2005. Non-alcoholic fatty liver disease and insulin resistance. Eur. J. Gastroenterol. Hepatol., 17(8):823–826. [doi:10.1097/00042737-200508000-00008]
Marchesini, G., Brizi, M., Bianchi, G., Tomassetti, S., Bugianesi, E., Lenzi, M., McCullough, A.J., Natale, S., Forlani, G., Melchionda, N., 2001. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes, 50(8):1844–1850.
Mehta, K., van Thiel, D.H., Shah, N., Mobarhan, S., 2002. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr. Rev., 60(9):289–293. [doi:10.1301/002966402320387224]
Poonawala, A., Nair, S.P., Thuluvath, P.J., 2000. Prevalence of obesity and diabetes in patients with cryptogenetic cirrhosis: a case control study. Hepatology, 32(4 Pt 1):689–692. [doi:10.1053/jhep.2000.17894]
Sanyal, A.J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W.B., Contos, M.J., Sterling, R.K., Luketic, V.A., Shiffman, M.L., Clore, J.N., 2001. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology, 120(5):1183–1192. [doi:10.1053/gast.2001.23256]
Sanyal, A.J., Mofrad, P.S., Contos, M.J., Sargeant, C., Luketic, V.A., Sterling, R.K., Stravitz, R.T., Shiffman, M.L., Clore, J., Mills, A.S., 2004. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepato., 2(12):1107–1115. [doi:10.1016/S1542-3565(04)00457-4]
Solomon, S.S., Usdan, L.S., Palazzolo, M.R., 2001. Mechanisms involved in TNF-α induction of insulin resistance and its reversal by TZD. Am. J. Med. Sci., 322(2):75–78. [doi:10.1097/00000441-200108000-00005]
Wang, J.T., Liu, Y.L., 2003. Non-alcoholic fatty liver disease: the problems we are facing. Hepatobiliary Pancreat. Dis. Int., 2(3):334–337.
Zhao, C.Y., Jiang, L.L., 2003. Peroxisome proliferators-activated receptor in liver disease. Chin. J. Hepatol., 11(6):382–384 (in Chinese).
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Xu, P., Zhang, Xg., Li, Ym. et al. Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats. J. Zhejiang Univ. - Sci. B 7, 627–633 (2006). https://doi.org/10.1631/jzus.2006.B0627
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DOI: https://doi.org/10.1631/jzus.2006.B0627