Hyodeoxycholic acid suppresses hepatic steatosis in a PPARα-dependent manner via distinct GLP-1- and iNKT cell-mediated pathways.

Hepatosteatosis is a common metabolic disorder. Bile acids influence hepatosteatosis, immune function, and incretin secretion. However, whether bile acids mediate hepatosteatosis through these immune or endocrine pathways remain unknown. Here, we identify supplementation with hyodeoxycholic acid (HDCA) in high-fat diet-fed mice increases hepatic iNKT cells and elevates circulating GLP-1, both upregulating fatty acid oxidation genes in a PPARα-dependent manner. Mechanistically, HDCA increases iNKT cells and IFN-γ production that promotes hepatic lipid catabolism, thereby attenuating triglyceride accumulation in wild-type (WT) mice, but not in iNKT cell-deficient (Ja18-/-) and PPARα knockout (Ppara-/-) mice. By contrast, the GLP-1 receptor agonist suppresses high-fat diet-induced steatosis in WT and Ja18-/- mice, but not in Ppara-/- and GLP-1 receptor knockout (Glp1r-/-) mice. Furthermore, anti-steatotic effect of HDCA is nullified in Glp1r-/- mice. Consequently, HDCA alleviates hepatosteatosis through dual mechanisms; an iNKT cell/IFN-γ immunometabolic- and GLP-1-dependent pathways. These findings highlight HDCA as a promising multi-target therapeutic strategy for hepatosteatosis.