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Histone H3K9 demethylase JMJD2B induces hepatic steatosis through upregulation of PPAR?2.

ABSTRACT: Understanding the epigenetic mechanisms underlying the progression of hepatic steatosis is important for identifying new therapeutic targets against nonalcoholic fatty liver disease (NAFLD). We investigated the functional role of histone demethylase JMJD2B in the pathologic regulation of hepatic steatosis. JMJD2B expression was markedly increased in HepG2 cells treated with palmitate and oleate or liver X receptor agonist T09013178 and in the liver of high-fat diet (HFD)-induced obese mice. Overexpression of JMJD2B using adenovirus in HepG2 cells stimulated the expression of peroxisome proliferator-activated receptor ?2 (PPAR?2) and its steatosis target genes associated with fatty acid uptake and lipid droplet formation, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, knocking down JMJD2B using siRNA reversed JMJD2B-mediated effects in HepG2 cells. The JMJD2B-dependent upregulation of PPAR?2 was associated with the removal of di- and trimethylation of histone H3 lysine 9 on the promoter of PPAR?2. Furthermore, exogeneous expression of JMJD2B using adenovirus in mice resulted in hepatic steatosis when fed a HFD, which was accompanied with increased expression of hepatic PPAR?2 and its steatosis target genes. Together, our results provide novel insights into the pivotal role of JMJD2B in the development of hepatic steatosis through upregulation of PPAR?2 and steatosis target genes.


PROVIDER: S-EPMC6137221 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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