Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition

Autor: Hyunsoo Cho, Sang Soo Kim, Young-Bum Kim, Min-Cheol Kang, Seung-Hwan Lee, Won Mo Yang, Hua Meng, Daehee Hwang, Ji A. Seo, Inês Sousa-Lima, Kyong Soo Park, Jinhyuk Bhin, Minho Shong, Yossi Dagon, Min Seon Kim, Byung Hong Chung, Morris F. White, John G. Jones, Bhavna N. Desai, Min Jeong Ryu, Peixin Li, Hu Huang, Getachew Debas Belew, Sungman Cho, Munehiko Shibata, Won Min Hwang, Maria Paula Macedo
Přispěvatelé: NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), Centro de Estudos de Doenças Crónicas (CEDOC)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Journal of Diabetes Investigation
Journal of Clinical Investigation
Popis: This work was supported by grants from the NIH (R01DK083567 to YBK), the American Diabetes Association (1-09-RA-87 to YBK), the American Heart Association (12GRANT12040170 to YBK), the East Carolina University Start-up fund (to HH), the National Research Foundation (NRF-2014M3A9D8034464 to M Shong, NRF-2016R1A2B3010373 to KSP, NRF-2015R1C1A1A02037164 to SHL), the National Research Foundation of Korea (2013M3C7A1056024 to MSK), and the Korean Diabetes Association (to JAS, 2017). In addition, structural funding for the Center for Neuroscience and Cell Biology, University of Coimbra, NMR facility is supported by FEDER-PT2020 (UID/BIA/04004/2013 and CENTRO-07-CT62-FEDER-002012) and by the Portuguese Foundation for Science and Technology (FCT) through grants PTDC/CVT-NUT/2851/2014, PTDC/BIM-MET/4265/2014, and RECI/QEQ-QFI/0168/2012. ISL is a recipient of an FCT fellowship from Portugal (SFRH/BD/71021/2010), and MCK is a recipient of a postdoctoral fellowship award from the American Diabetes Association (1-17-PDF-146). GDB is supported by the European Union's Horizon 2020 Research and Innovation programme under Marie Sklodowska-Curie Grant Agreement 722619. We thank Farhad Danesh for CA-ROCK1-knockin mice; Huseyin Ozkan, Ivan Viegas, Cristina Barosa, Hyun Cheol Rho, Xuemei Ma, Yao Yang, and Alexander Banks for technical help; and Barbara Kahn, Tony Hollenberg, Sonia Najjar, and Terry Flier for helpful discussion. 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. publishersversion published
Databáze: OpenAIRE
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