Inflammation promotes hepatic but not adipose tissue DGAT2 expression and triglyceride synthesis in MAFLD mice.

Abstract

This study primarily aimed to investigate whether superimposed inflammation in metabolic dysfunction associated fatty liver disease (MAFLD) enhances the expression of triglyceride (TG) synthesizing enzymes, acyl-CoA: diacylglycerol acyltransferase (DGAT) 1&2 expression, and the associated TG synthesis in hepatic and adipose tissues. Secondly, we examined the effects of the FXR agonist obeticholic acid (OCA; also known as INT-747) and a DGAT2 inhibitor on the regulation of the hepatic DGAT-TG pathway in MAFLD with and without LPS. After 90 days of feeding with either a high-fat diet (HFD) or standard chow, mice were orally administered INT-747 or a DGAT2 inhibitor (DGAT2i) for two weeks. In addition, treatment groups received lipopolysaccharide (LPS) to assess the impact of superimposed inflammation in the context of fatty liver. HFD-induced MAFLD mice exhibited significantly elevated hepatic and adipose tissue expression of DGAT1 and DGAT2 compared with chow-fed controls. LPS administration to MAFLD mice led to a further marked increase in hepatic DGAT2 expression and hepatic TG levels, while hepatic DGAT1 and adipose tissue DGAT1/2 expression remained unchanged. Treatment with either INT -747 or DGAT2i in MAFLD mice (±LPS) resulted in reduced hepatic and plasma TG levels, accompanied by decreased DGAT 1 and DGAT 2 expression. Our findings highlight a strong association between markedly elevated hepatic, but not adipose tissue, DGAT2 expression and increased TG synthesis in MAFLD mice with superimposed inflammation. Treatment with INT-747 or DGAT2i mitigated hepatic steatosis progression by suppressing hepatic DGAT2 overexpression and TG synthesis. Therefore, these agents may represent potential therapeutic strategies for managing MAFLD in the presence of inflammation.