Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Department of Kinesiology and Physiology, East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, North Carolina, USA.
J Clin Invest. 2018 Dec 3;128(12):5335-5350. doi: 10.1172/JCI63562. Epub 2018 Oct 29.
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.
肥胖是导致非酒精性脂肪性肝病（NAFLD）的一个主要危险因素。NAFLD 是最常见的慢性肝病形式，与胰岛素抵抗密切相关，最终导致肝硬化和肝细胞癌。然而，对于肥胖相关脂肪性肝病的细胞内调节因子的了解仍不完整。在这里，我们表明肝 Rho-激酶 1（ROCK1）通过刺激从头脂肪生成来驱动肥胖引起的小鼠脂肪肝。由于能量消耗和产热基因表达增加，肝脏中缺乏 ROCK1 的小鼠对饮食诱导的肥胖具有抗性。肝 ROCK1 的组成型表达足以促进高脂肪饮食喂养的小鼠的肥胖、胰岛素抵抗和肝脂质蓄积。相应地，肝特异性 ROCK1 缺失可防止肥胖糖尿病（ob/ob）小鼠发生严重的肝脂肪变性和降低高血糖。具有病理生理学意义的是，患有脂肪肝的人类肝脏 ROCK1 明显上调，并与聚集在非酒精性脂肪性肝病和胰岛素抵抗周围的危险因素相关。从机制上讲，我们发现肝 ROCK1 抑制 AMPK 活性，并且 ROCK1/AMPK 途径是介导肝中大麻素诱导的脂肪生成所必需的。此外，最广泛使用的抗糖尿病药物二甲双胍通过失活 ROCK1 减少肝脂质积累，从而激活 AMPK 下游信号。总之，我们的研究结果确立了一个 ROCK1/AMPK 信号轴，该信号轴调节从头脂肪生成，为治疗肥胖相关代谢紊乱（如非酒精性脂肪性肝病）提供了一个独特的靶点。
