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

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dc.contributor.authorKyung Hee Noh-
dc.contributor.authorHyun Mi Kang-
dc.contributor.authorW Yoo-
dc.contributor.authorYoohong Min-
dc.contributor.authorDaehun Kim-
dc.contributor.authorMijin Kim-
dc.contributor.authorSihyung Wang-
dc.contributor.authorJung Hwa Lim-
dc.contributor.authorCho Rok Jung-
dc.date.accessioned2020-09-24T03:45:28Z-
dc.date.available2020-09-24T03:45:28Z-
dc.date.issued2020-
dc.identifier.issn00260495-
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/22741-
dc.description.abstractBackground: 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.-
dc.publisherElsevier-
dc.titleUbiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression-
dc.title.alternativeUbiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression-
dc.typeArticle-
dc.citation.titleMetabolism-Clinical and Experimental-
dc.citation.number0-
dc.citation.endPage154302-
dc.citation.startPage154302-
dc.citation.volume110-
dc.contributor.affiliatedAuthorKyung Hee Noh-
dc.contributor.affiliatedAuthorHyun Mi Kang-
dc.contributor.affiliatedAuthorYoohong Min-
dc.contributor.affiliatedAuthorDaehun Kim-
dc.contributor.affiliatedAuthorMijin Kim-
dc.contributor.affiliatedAuthorSihyung Wang-
dc.contributor.affiliatedAuthorJung Hwa Lim-
dc.contributor.affiliatedAuthorCho Rok Jung-
dc.contributor.alternativeName노경희-
dc.contributor.alternativeName강현미-
dc.contributor.alternativeName유원백-
dc.contributor.alternativeName민유홍-
dc.contributor.alternativeName김대훈-
dc.contributor.alternativeName김미진-
dc.contributor.alternativeName왕시형-
dc.contributor.alternativeName임정화-
dc.contributor.alternativeName정초록-
dc.identifier.bibliographicCitationMetabolism-Clinical and Experimental, vol. 110, pp. 154302-154302-
dc.identifier.doi10.1016/j.metabol.2020.154302-
dc.subject.keywordVon Hippel-Lindau-
dc.subject.keywordLipid metabolism-
dc.subject.keywordUbiquitination-
dc.subject.keywordACLY-
dc.subject.keywordPPAR-gamma-
dc.subject.localVon Hippel-Lindau-
dc.subject.localVon Hippel Lindau (VHL)-
dc.subject.localLipid metabolism-
dc.subject.localUbiquitination-
dc.subject.localACLY-
dc.subject.localPPAR-gamma-
dc.subject.localPPAR-γ-
dc.description.journalClassY-
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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