[논문]Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression

Noh, Kyung Hee; Kang, Hyun Mi; Yoo, Wonbeak; Min, Yoohong; Kim, Daehun; Kim, Mijin; Wang, Sihyung; Lim, Jung Hwa; Jung, Cho-Rok

doi:10.1016/j.metabol.2020.154302

[해외논문] Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression

Metabolism : clinical and experimental, v.110, 2020년, pp.154302 -

Noh, Kyung Hee (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kang, Hyun Mi (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Yoo, Wonbeak (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Min, Yoohong (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kim, Daehun (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kim, Mijin (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Wang, Sihyung (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Lim, Jung Hwa (Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Jung, Cho-Rok (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

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Abstract 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. Highlights VHL inhibits ACLY transcription via regulating the binding of PPARγ to its PPRE site in the ACLY promoter. pVHL targets PPARγ for degradation by the ubiquitin-proteasome pathway. Overexpression of VHL restored hepatic steatosis in a mouse steatosis model. VHL/ACLY axis is implicated in tumor progression in vitro and in vivo

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DOI : 10.1016/j.metabol.2020.154302
WB Saunders : 저널
Elsevier : 저널 > 논문

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