Enhancer of zeste homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation

Role of apolipoprotein e

Nicole K.H. Yiew, Charlotte Greenway, Abdalrahman Zarzour, Samah Ahmadieh, Brandee Goo, David Kim, Tyler W. Benson, Mourad Ogbi, Yao Liang Tang, Weiqin Chen, David W Stepp, Vijaykumar Surendrakant Patel, Renee Hilton, Xinyun Lu, David Y. Hui, Ha Won Kim, Neal Lee Weintraub

Research output: Contribution to journalArticle

Abstract

Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that plays a key role in cell differentiation and oncogenesis, was reported to promote adipogenic differentiation in vitro by catalyzing trimethylation of histone 3 lysine 27. However, inhibition of EZH2 induced lipid accumulation in certain cancer and hepatocyte cell lines. To address this discrepancy, we investigated the role of EZH2 in adipogenic differentiation and lipid metabolism using primary human and mouse preadipocytes and adipose- specific EZH2 knockout (KO) mice. We found that the EZH2-selective inhibitor GSK126 induced lipid accumulation in human adipocytes, without altering adipocyte differentiation marker gene expression. Moreover, adipocyte-specific EZH2 KO mice, generated by crossing EZH2 floxed mice with adiponectin- Cre mice, displayed significantly increased body weight, adipose tissue mass, and adipocyte cell size and reduced very low-density lipoprotein (VLDL) levels, as compared with littermate controls. These phenotypic alterations could not be explained by differences in feeding behavior, locomotor activity, metabolic energy expenditure, or adipose lipolysis. In addition, human adipocytes treated with either GSK126 or vehicle exhibited comparable rates of glucose-stimulated triglyceride accumulation and fatty acid uptake. Mechanistically, lipid accumulation induced by GSK126 in adipocytes was lipoprotein-dependent, and EZH2 inhibition or gene deletion promoted lipoprotein-dependent lipid uptake in vitro concomitant with up-regulated apolipoprotein E (ApoE) gene expression. Deletion of ApoE blocked the effects of GSK126 to promote lipoprotein- dependent lipid uptake in murine adipocytes. Collectively, these results indicate that EZH2 inhibition promotes lipoprotein-dependent lipid accumulation via inducing ApoE expression in adipocytes, suggesting a novel mechanism of lipid regulation by EZH2.

Original languageEnglish (US)
Pages (from-to)8577-8591
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number21
DOIs
StatePublished - Jan 1 2019

Fingerprint

Apolipoproteins
Lipid Metabolism
Adipocytes
Lipids
Lipoproteins
Apolipoproteins E
Gene expression
Knockout Mice
VLDL Lipoproteins
Adiponectin
Differentiation Antigens
Enhancer of Zeste Homolog 2 Protein
Histones
Gene Expression
Lysine
Triglycerides
Lipolysis
Fatty Acids
Gene Deletion
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Enhancer of zeste homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation : Role of apolipoprotein e. / Yiew, Nicole K.H.; Greenway, Charlotte; Zarzour, Abdalrahman; Ahmadieh, Samah; Goo, Brandee; Kim, David; Benson, Tyler W.; Ogbi, Mourad; Tang, Yao Liang; Chen, Weiqin; Stepp, David W; Patel, Vijaykumar Surendrakant; Hilton, Renee; Lu, Xinyun; Hui, David Y.; Kim, Ha Won; Weintraub, Neal Lee.

In: Journal of Biological Chemistry, Vol. 294, No. 21, 01.01.2019, p. 8577-8591.

Research output: Contribution to journalArticle

Yiew, Nicole K.H. ; Greenway, Charlotte ; Zarzour, Abdalrahman ; Ahmadieh, Samah ; Goo, Brandee ; Kim, David ; Benson, Tyler W. ; Ogbi, Mourad ; Tang, Yao Liang ; Chen, Weiqin ; Stepp, David W ; Patel, Vijaykumar Surendrakant ; Hilton, Renee ; Lu, Xinyun ; Hui, David Y. ; Kim, Ha Won ; Weintraub, Neal Lee. / Enhancer of zeste homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation : Role of apolipoprotein e. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 21. pp. 8577-8591.
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