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

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.

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…In MAFLD, the repressive histone marks (H3K9me2 and H3K9me3) near LXRE in the promoter region of LXRαtarget genes were removed by histone demethylase Jumonji domain-containing protein 2B (JMJD2B) (Table 1; Figure 2) (Kim et al, 2020). These alterations lead to increased expression of hepatic LXRα-dependent lipogenic genes, which contribute to the development of hepatic steatosis (Kim et al, 2020). Besides, transgenerational high-fat diet (HFD) feeding reduced H3K9me2…”

“…After binding of the ligand, LXR would translocate to the nucleus and activate the transcription of genes containing LXR response elements ( LXREs ) ( Slominski et al, 2021 ). In MAFLD, the repressive histone marks (H3K9me2 and H3K9me3) near LXRE in the promoter region of LXRα-target genes were removed by histone demethylase Jumonji domain-containing protein 2B (JMJD2B) ( Table 1 ; Figure 2 ) ( Kim et al, 2020 ). These alterations lead to increased expression of hepatic LXRα-dependent lipogenic genes, which contribute to the development of hepatic steatosis ( Kim et al, 2020 ).…”

“…In MAFLD, the repressive histone marks (H3K9me2 and H3K9me3) near LXRE in the promoter region of LXRα-target genes were removed by histone demethylase Jumonji domain-containing protein 2B (JMJD2B) ( Table 1 ; Figure 2 ) ( Kim et al, 2020 ). These alterations lead to increased expression of hepatic LXRα-dependent lipogenic genes, which contribute to the development of hepatic steatosis ( Kim et al, 2020 ). Besides, transgenerational high-fat diet (HFD) feeding reduced H3K9me2 accumulation at promoters of LX Rα and endoplasmic reticulum oxidoreductin-alpha (ERO1-α) in the offspring mice, which account for the up-regulation of lipogenesis and endoplasmic reticulum (ER) stress in the development of obesity and hepatic steatosis ( Li et al, 2012 ).…”

Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease

“…JMJD2B was shown to play a role in the development of hepatic steatosis through upregulation of PPARγ2 and steatosis target genes including CD36 and fatty acid-binding protein [ 105 ]. Not long ago, Kim et al provided evidence that JMJD2B induces LXRα-dependent lipogenesis by removing repressive histone marks H3K9me2 and H3K9me3 near LXREs of lipogenic gene promoters leading to the development of NAFLD [ 126 ]. Moreover, an additional H3K9 HDM, Plant homeodomain finger protein 2 (Phf2), was shown to erase H3K9me2 methyl-marks on the promoter of carbohydrate-responsive element-binding protein, (ChREBP) thereby protects liver from the pathogenesis progression of NAFLD [ 127 ].…”

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

“…LXRs activity is subtly regulated by the interaction with the nuclear receptor co-repressors (NCoR) or the nuclear receptor coactivators protein complex (8) upon specific agonist activation. Recent evidences are now showing the emerging role of some methylase/demethylase enzymes in the modulation of LXR activity through the chromatin packaging and subsequent availability, adding one more complex layer of regulation (9,10).…”