Hyodeoxycholic Acid Suppresses Hepatosteatosis via GLP-1/iNKT Cell Crosstalk and PPARα Activation (scRNAseq_primary hepatocytes)

Hepatosteatosis, a common liver condition, involves excessive lipid accumulation and can lead to severe complications. Its molecular mechanisms are poorly understood, highlighting the need for therapies. The molecular mechanisms are poorly understood, emphasizing the need for effective therapies. In this study, we identified hyodeoxycholic acid (HDCA) as a potent anti-steatotic agent capable of preventing diet-induced fatty liver. Mechanistically, HDCA treatment enhanced the hepatic expression of numerous PPARα target genes while also promoting the secretion of the gut hormone GLP-1. The significance of PPARα signalling was emphasised by the fact that the anti-steatotic effects of HDCA were completely abolished in PPARα-knockout mice. Our findings further reveal a novel mechanism involving invariant natural killer T (iNKT) cells. HDCA treatment increased both the number and proliferation of iNKT cells in vivo, a phenomenon recapitulated in vitro using a GLP-1 agonist. This indicates that the anti-steatotic action of HDCA requires the coordinated activity of PPARα signalling and iNKT cells. These insights offer a promising avenue for developing targeted therapies for MASLD.