Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Hu Huang, … , John Jones, Young-Bum Kim
Hu Huang, … , John Jones, Young-Bum Kim
Published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5335-5350. https://doi.org/10.1172/JCI63562.
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Research Article Endocrinology Metabolism

Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition

Abstract

Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity owing to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiological significance, hepatic ROCK1 was markedly upregulated in humans with fatty liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1/AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used antidiabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1/AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.

Authors

Hu Huang, Seung-Hwan Lee, Inês Sousa-Lima, Sang Soo Kim, Won Min Hwang, Yossi Dagon, Won-Mo Yang, Sungman Cho, Min-Cheol Kang, Ji A. Seo, Munehiko Shibata, Hyunsoo Cho, Getachew Debas Belew, Jinhyuk Bhin, Bhavna N. Desai, Min Jeong Ryu, Minho Shong, Peixin Li, Hua Meng, Byung-Hong Chung, Daehee Hwang, Min Seon Kim, Kyong Soo Park, Maria Paula Macedo, Morris White, John Jones, Young-Bum Kim

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Figure 1

ROCK1 expression and activation increase in the liver of animal models with obesity and in humans with fatty liver disease.

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ROCK1 expression and activation increase in the liver of animal models w...
(A) Hepatic ROCK1 expression in mice fed a normal chow diet or an HFD at 18 weeks of age (n = 5 per group). (B–D) Hepatic ROCK1 activity in HFD-fed mice (18 weeks of age, n = 5 per group) (B), ob/ob mice (10 weeks of age, n = 5 per group) (C), and db/db mice (10 weeks of age, n = 5 per group) (D). Mice were fed either a normal chow diet or an HFD for 12 weeks from 6 weeks of age. Liver lysates (30 μg) were separated by SDS-PAGE. ROCK1 was visualized by immunoblotting and quantitated by densitometry. ROCK1 activity in liver lysates (300 μg) was measured by immune complex assay. (E) Hepatic ROCK1 expression in humans with or without fatty liver disease (n = 9−10 per group). (F) Relationship between hepatic ROCK1 levels and BMI, serum triglyceride, alanine transaminase (ALT), and aspartate transaminase (AST) levels in humans with or without fatty liver disease. Relationships were statistically analyzed by Pearson correlation coefficient. (G) Oil Red O–stained liver sections in humans with or without fatty liver disease. Scale bars: 100 μm. Values are means ± SEM. **P < 0.01 vs. chow, lean, or control (non–fatty liver human) by unpaired Student’s t test.