ArticleThe Journal of clinical investigation2018
Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 90 citations in OpenAlex.
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- ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.Acta pharmacologica Sinica · 2024Article
- Mechanical activation of VE-cadherin stimulates AMPK to increase endothelial cell metabolism and vasodilation.bioRxiv : the preprint server for biology · 2024Article
- The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review.European journal of clinical pharmacology · 2024Review
- Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism.Communications biology · 2023Article
- MicroRNA regulation of AMPK in nonalcoholic fatty liver disease.Experimental & molecular medicine · 2023Review
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27 authors at 11 institutions in 4 countries.
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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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.