Histone modifications in fatty acid synthase modulated by carbohydrate responsive element binding protein are associated with non‑alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and is closely associated with diabetes; however, its pathogenesis remains to be elucidated. Carbohydrate responsive element binding protein (ChREBP), the hub of glucolipid metabolism, regulates the induction of fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, by directly binding to carbohydrate response element (ChoRE) in its promoter. Investigations of histone modifications on NAFLD remain in their infancy. In the present study, by using ChIP, the association between histone modifications and FASN transcription was investigated and histone modifications in FASN modulated by ChREBP were measured. It was demonstrated that ChREBP induced FASN ChREBP-ChoRE binding to accelerate the expression of FASN, leading to hepatocellular steatosis by facilitating H3 and H4 acetylation, H3K4 trimethylation and the phosphorylation of H3S10, but inhibiting the trimethylation of H3K9 and H4K20 in FASN promoter regions of HepG2 and L02 cells. It was also found that ChREBP-ChoRE binding of FASN relied on histone acetylation and that the transcriptional activity of ChREBP on FASN is required, based on the premise that histone acetylation causes conformational changes in FASN chromatin. This indicated histone acetylation as a crucial mechanism involved in the transcription of FASN modulated by ChREBP. Consequently, the present study provides further insight into the pathophysiology and a novel therapeutic potential of NAFLD based on epigenetic mechanisms.

FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice

“…Thus, like other HDAC inhibitors (53,54,74), reduction in FASN could be due to inhibition of HDACs by FTY720-P and increased H3K9 acetylation. These findings are in agreement with a recent report showing that the expression of Fasn in the liver is associated with increased H3K9 acetylation that modulates the binding of carbohydrate responsive element binding protein to the promoter/enhancer region of the Fasn gene (75).…”

ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

“…The transcriptional activity of ChREBP is activated by glucosederived metabolites such as glucose-6-phosphate, xylulose-5phophate, and fructose-2,6-bisphosphate via regulation of its nucleocytoplasmic translocation (62)(63)(64)(65). Moreover, ChREBP transcription activity is also regulated by acetyl CoA and uridine diphosphate-N-acetylglucosamine, through acetylation and O-GlcNAcylation, respectively (66)(67)(68)(69)(70)(71)(72)(73). These substances are involved in epigenic regulation, such as histone acetylation and histone methylation (Figure 1).…”

“…During weaning, Fasn mRNA expression is increased by greater binding of ChREBP and SREBP-1c to Fasn promoter and greater histone H3 and H4 acetylation ( 70 ). Moreover, ChREBP induces Fasn mRNA expression and triglyceride synthesis by facilitating H3 and H4 acetylation, but these effects are prevented by the inhibition of histone acetylation using garcinol, a histone acetyltransferase (HAT) inhibitor ( 71 ). The role of the histone deacetylase activity of CREB-binding protein (CBP)/p300 in the mechanism of ChREBP-induced histone acetylation is well known ( 72 ).…”

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…This gives us a clue that the acetylation of H3K9/K18 induced by obesity can activate the transcription of pro-inflammatory-related genes, triggering or aggravating the inflammatory responses in MAFLD. With insulin stimulation, H3, H4 hyperacetylation (H3K4, H3K9, and H4K20) was found in the promoter of fatty acid synthase ( FASN ), sterol regulatory elements ( SRE ), and carbohydrate-responsive elements ( ChoRE ) ( Table 1 ), which function in the de novo of lipogenesis, cholic acid synthesis, and cholesterol absorption, and lipogenic and glycolytic, respectively ( Du et al, 2017 ; Cai et al, 2018 ; Rohrbach et al, 2019 ). Similarly, H4K8ac and H4K16ac were also accompanied by increased HAT activity in HepG2 cells with lipid accumulation ( Table 1 ; Figure 2 ) ( Chung et al, 2019 ).…”