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 γ2 (PPARγ2) 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 PPARγ2 was associated with the removal of di- and trimethylation of histone H3 lysine 9 on the promoter of PPARγ2. 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 PPARγ2 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 PPARγ2 and steatosis target genes.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder and an emerging health concern worldwide
We investigated the functional role of histone demethylase JMJD2B in pathologic mechanisms by which nonalcoholic fatty liver disease (NAFLD) is developed
We found that JMJD2B promotes peroxisome proliferator-activated receptor γ2 (PPARγ2) expression by removing repressive H3K9me[2] and H3K9me[3] marks on the promoter of PPARγ2, which subsequently increases the expression of PPARγ2 steatosis target genes and results in the development of hepatic steatosis
Summary
Nonalcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder and an emerging health concern worldwide. The JMJD2 or KDM4 family consists of JMJD2A (KDM4A), JMJD2B (KDM4B), and JMJD2C (KDM4C) They demethylate di- and trimethylated H3K9 and H3K36 The histone H3K4 methyltransferase MLL4 enhances the expression of PPARγ2 and its hepatosteatosis target genes and results in the induction of hepatic steatosis[18]. Histone deacetylase[3] (HDAC3) binds to retinoic acid receptor-related orphan receptor α (RORα) on the promoter of PPARγ2 and represses PPARγ2 expression in hepatocytes, thereby protecting against diet-induced hepatic steatosis[19]. We previously reported that JMJD2B promotes PPARγ2 expression via erasing H3K9me2/me[3] on the PPARγ2 promoter, which stimulates adipogenesis in 3T3-L1 preadipocytes[20]; the role of JMJD2B in the development of hepatic steatosis has not been elucidated
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