Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor

作者：Hung‐Yun Lin, I-Chen Ivorine Yu, Ruey-Shen Wang, Yei‐Tsung Chen, Ning-Chun Liu, Saleh Altuwaijri, Cheng–Lung Hsu, Wen‐Lung Ma, Jenny D. Jokinen, Janet D. Sparks, Shuyuan Yeh, Chawnshang Chang · 发表于：Hepatology · 年份：2008 · DOI：10.1002/hep.22252 · 被引用次数：209 · 研究领域：Hormonal and reproductive studies、Sexual Differentiation and Disorders、Diabetes, Cardiovascular Risks, and Lipoproteins

UNLABELLED: Early studies demonstrated that whole-body androgen receptor (AR)-knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR-knockout (H-AR(-/y)) mice and found that male H-AR(-/y) mice, but not female H-AR(-/-) mice, fed a high-fat diet developed hepatic steatosis and insulin resistance, and aging male H-AR(-/y) mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H-AR(-/y) mice resulted from decreased fatty acid beta-oxidation, increased de novo lipid synthesis arising from decreased PPARalpha, increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat-fed H-AR(-/y) mice was associated with decreased phosphoinositide-3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein-tyrosine phosphatase 1B expression. CONCLUSION: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men.