Background

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.

Findings

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.

Conclusions

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.

中文翻译：

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pVHL对PPAR-γ的泛素化抑制ACLY表达和脂质代谢，与肿瘤进展有关。

背景

细胞内脂质积累与多种疾病，特别是癌症有关。线粒体功能障碍被认为是脂质堆积的原因。但是，相关的潜在机制仍不清楚。

发现

我们发现Von Hippel-Lindau（VHL）缺陷导致肾细胞癌细胞中脂质蓄积和线粒体功能障碍。此外，VHL在转录水平上下调了ATP柠檬酸裂解酶（ACLY），它是从头合成脂质的关键酶，在转录水平上抑制了人类肾癌组织中细胞内脂质的积累。我们通过与启动子上的顺式调控位点PPRE结合，将PPARγ识别为调控ACLY表达的转录因子。VHL直接相互作用与和促进PPARγ的泛素化，导致其降解二者在体外和在体内，导致ACLY的下调。此外，腺病毒介导的VHL过表达显着改善了高脂饮食诱导的肝脂肪变性。db / db鼠标。重要的是，在《癌症基因组图集》的数据集中，低VHL表达与高表达ACLY和人类肝癌预后不良有关。

结论

VHL通过调节线粒体和靶向PPARγ来参与细胞脂质代谢，PPARγ是ACLY的转录因子，独立于缺氧诱导因子1α。揭示了一种新型的VHL-PPARγ-ACLY轴及其在脂肪肝疾病和癌症中的意义。