脂肪变性
脂滴
非酒精性脂肪肝
脂肪肝
甘油三酯
泛素
基因亚型
生物
化学
生物化学
内科学
基因
内分泌学
疾病
胆固醇
医学
作者
Soumik BasuRay,Yan Wang,Ēriks Šmagris,Jonathan C. Cohen,Helen H. Hobbs
标识
DOI:10.1073/pnas.1901974116
摘要
Significance A sequence variant (I148M) in PNPLA3 is a major genetic risk factor for nonalcoholic fatty liver disease. Previously, we showed that PNPLA3(148M) evades ubiquitylation-mediated degradation and accumulates to high levels on lipid droplets (LDs). Here we address how this accumulation is related to steatosis. We generated an active, ubiquitylation-resistant isoform that accumulated on LDs and increased hepatic triglyceride levels when expressed in livers of mice. Conversely, depletion of PNPLA3 resolved the excess hepatic fat accumulation associated with expression of PNPLA3(148M). Our results provide direct evidence that accumulation of PNPLA3 per se causes fatty liver, and that depletion of the protein is a potential strategy for therapeutic intervention.
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