PDF(Pubmed)
Abstract：
Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.
摘要：
肝性脂肪变性,以肝脏中脂质过度积累为特征，是现代社会的重大健康问题。了解如何改变肝脂代谢/体内平衡导致肝骨病有助于制定治疗干预措施。先前的研究确定线粒体功能障碍是肝骨化的原因。但是,线粒体功能障碍导致脂质代谢改变的分子机制尚不完全清楚。我们之前的工作表明Rheb,一种类似于Ras的小GTPase,不仅激活mTORC1，而且通过丙酮酸脱氢酶（PDH）促进线粒体ATP的产生。在这项研究中,我们进一步证明Rheb控制肝脏甘油三酯分泌并减少小鼠肝脏中饮食诱导的脂质积累。Rheb的遗传缺失导致肝脏快速和自发的脂肪变性，这是意想不到的mTORC1的作用，增强脂质合成，而Rheb转基因可显着减少饮食诱导的肝骨化。结果表明，RhebKO的肝骨病是脂质分泌受损的结果，这与肝细胞的线粒体ATP产生有关。我们的发现强调了Rheb在通过线粒体能量产生调节肝脂质分泌中的作用，具有治疗意义。
