PDF(Pubmed)
Abstract：
The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.
摘要：
PNPLA3的I148M变体与肝性脂肪变性密切相关。最近的证据表明，I148M突变体作为PNPLA2/ATGL介导的脂解的抑制剂，留下野生型PNPLA3的作用未定义。尽管在体外显示出甘油三酯水解酶活性，尚未将PNPLA3确立为体内脂肪酶。这里,我们表明PNPLA3优先水解多不饱和甘油三酯，动员多不饱和脂肪酸用于磷脂去饱和和增强富含甘油三酯的脂蛋白的肝脏分泌。在生脂条件下，肝脏特异性敲除或急性敲除PNPLA3的小鼠表现出加重的肝脏脂肪变性和降低的血浆VLDL-甘油三酯水平。同样，I148M敲入小鼠在脂肪生成刺激期间显示肝甘油三酯分泌减少。我们的结果突出了一个特定的背景，即野生型PNPLA3促进肝脏甘油三酯储存和分泌之间的平衡，并提出了I148M变体功能丧失对人类脂肪肝疾病发展的潜在贡献。
