ATP柠檬酸裂解酶
脂质代谢
转录因子
下调和上调
脂肪变性
生物
癌症研究
过氧化物酶体增殖物激活受体
脂滴
线粒体
脂肪肝
细胞生物学
内分泌学
化学
内科学
生物化学
柠檬酸合酶
医学
受体
酶
基因
疾病
作者
Kyung Hee Noh,Hyun Mi Kang,Wonbeak Yoo,Yoo-Hong Min,Daehun Kim,Mijin Kim,Sihyung Wang,Jung Hwa Lim,Cho‐Rok Jung
标识
DOI:10.1016/j.metabol.2020.154302
摘要
Intracellular lipid accumulation is associated with various diseases, particularly cancer. Mitochondrial dysfunction is considered as a cause of lipid accumulation; however, the related underlying mechanism remains unclear.We found that Von Hippel-Lindau (VHL)-deficiency led to lipid accumulation and mitochondrial dysfunction in renal cell carcinoma cells. Moreover, VHL downregulated ATP-citrate lyase (ACLY), a key enzyme in de novo lipid synthesis, at the transcriptional level, which inhibited intracellular lipid accumulation in human renal carcinoma tissues. We identified PPARγ as the transcription factor regulating ACLY expression by binding to the cis-regulatory site PPRE on its promoter. VHL directly interacted with and promoted ubiquitination of PPARγ, leading to its degradation both in vitro and in vivo, resulting in the downregulation of ACLY. Furthermore, adenovirus-mediated VHL overexpression substantially ameliorated hepatic steatosis induced by a high-fat diet in db/db mice. Importantly, low VHL expression was associated with high ACLY expression and poor prognosis in human liver carcinoma in a dataset in The Cancer Genome Atlas.VHL plays role in cellular lipid metabolism via regulating mitochondria and targeting PPARγ, a transcription factor for ACLY independent of hypoxia-inducible factor 1α. A novel VHL-PPARγ-ACLY axis and its implication in fatty liver disease and cancer were uncovered.
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