Format

Send to

Choose Destination
J Clin Invest. 2018 Dec 3;128(12):5335-5350. doi: 10.1172/JCI63562. Epub 2018 Oct 29.

Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition.

Author information

1
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Kinesiology and Physiology, East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, North Carolina, USA.
3
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
4
Centro de Estudos de Doenҫas Crónicas (CEDOC), Chronic Disease Research Center, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
5
Division of Endocrinology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
6
Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, Coimbra, Portugal.
7
Center for Plant Aging Research and Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea.
8
Department of Endocrinology and Metabolism, Chungnam National University School of Medicine, Daejeon, Korea.
9
Department of Comprehensive Surgery Medical and Health Center Beijing Friendship Hospital, Capital Medical University, Beijing, China.
10
Department of Nutrition Science, Diabetes Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
11
Department of Internal Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
12
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
13
Department of Endocrinology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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.

KEYWORDS:

Endocrinology; Glucose metabolism; Metabolism; Obesity

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center