Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis.

Ji-Hyun Kim,Dae Young Jung,Myeong Ho Jung,Hye-Ran Kim

doi:10.3390/ijms21218313

Ji-Hyun Kim, Dae Young Jung + Show 2 more

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https://doi.org/10.3390/ijms21218313

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Abstract

Ligand-activated liver X receptor α (LXRα) upregulates the expression of hepatic lipogenic genes, which leads to triglyceride (TG) accumulation, resulting in nonalcoholic fatty liver disease (NAFLD). Thus, LXRα regulation may provide a novel therapeutic target against NAFLD. However, histone methylation-mediated epigenetic regulation involved in LXRα-dependent lipogenesis is poorly understood. In this study, we investigated the functional role of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in LXRα-dependent lipogenesis. JMJD2B expression level was upregulated in HepG2 cells treated with LXRα agonist T0901317 or palmitate and the liver of mice administered with T0901317 or fed a high-fat diet. Knockdown of JMJD2B using siRNA abrogated T0901317-induced LXRα-dependent lipogenic gene expression and lowered intracellular TG accumulation. Conversely, overexpression of JMJD2B in HepG2 cells upregulated the expression of LXRα-dependent lipogenic genes, in line with increased intracellular TG levels. JMJD2B overexpression or T0901317 treatment induced the recruitment of JMJD2B and LXRα to LXR response elements (LXRE) in the promoter region of LXRα-target gene and reduced the enrichment of H3K9me2 and H3K9me3 in the vicinity of the LXRE. Furthermore, JMJD2B enhanced T0901317 or LXRα-induced transcriptional activities of reporters containing LXRE. A co-immunoprecipitation assay revealed that JMJD2B interacted with activated LXRα. Moreover, overexpression of JMJD2B in mice resulted in upregulation of hepatic LXRα-dependent lipogenic genes, consistent with development of hepatic steatosis. Taken together, these results indicate that JMJD2B plays a role in LXRα-mediated lipogenesis via removing the repressive histone marks, H3K9me2 and H3K9me3, at LXRE, which might contribute to hepatic steatosis.

Highlights

Nonalcoholic fatty liver disease (NAFLD), an etiology of chronic liver disease, involves hepatic steatosis, steatohepatitis, and cirrhosis and is associated with metabolic disorders including insulin resistance, type 2 diabetes, and obesity [1]
de novo lipogenesis (DNL) is stimulated by lipogenic transcription factors including sterol regulatory element-binding protein-1c (SREBP-1c; gene SREBF1), carbohydrate responsive element binding protein (ChREBP), and liver X receptor (LXR; gene NR1H3), which positively regulate the expression of lipogenic genes including fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and stearoyl-CoA desaturase 1 (SCD1)
Overexpression of JMJD2B reduced H3K9me2 and H3K9me3 enrichment in the same location, indicating that JMJD2B removes the repressive histone marks H3K9me2 and H3K9me3 at LXR response elements (LXRE) of the SREBF1 promoter. These results were consistent with those in liver X receptor α (LXRα) agonist-treated HepG2 cells, which showed an increased enrichment of JMJD2B and LXRα in the vicinity of LXREs on the SREBF1 promoter coupled with reduced levels of histone H3K9me2 and H3K9me3. These results suggest that the activation of LXRα induces the recruitment of JMJD2B to the LXRE of LXRα-dependent lipogenic genes, which subsequently leads to the removal of repressive histone marks H3K9me2 and H3K9me3 and results in the stimulation of LXRα-dependent lipogenesis

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), an etiology of chronic liver disease, involves hepatic steatosis, steatohepatitis, and cirrhosis and is associated with metabolic disorders including insulin resistance, type 2 diabetes, and obesity [1]. A hallmark of NAFLD, is caused by an imbalance in triglyceride (TG) synthesis, including de novo lipogenesis (DNL), the uptake of free fatty acids from adipose tissue or diet, and TG removal via fatty acid oxidation, very low-density lipoprotein (VLDL) secretion, and lipophagy [2]. Excess DNL can contribute to the development of NAFLD through the overproduction of fatty acids [2]. Studies on the role of epigenetics in the regulation of hepatic lipogenesis have been performed [3]. Epigenetic regulation of lipogenesis through histone methylation is poorly understood

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