Coagulation protease-activated receptor-2 (PAR2) promotes dyslipidemia, obesity and MASLD through repression of the hepatic pioneer factor HNF4α

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe version, metabolic dysfunction-associated steatohepatitis (MASH), are associated with obesity, dyslipidemia, diabetes, and atherothrombosis for reasons that are not well understood. Protease-activated receptor 2 (PAR2), a receptor activated by coagulation proteases that are dysregulated in inflammatory and fibrotic diseases, is emerging as a new drug target for MASH. METHODS: We conducted a cross-sectional study of liver specimens from patients who were obese vs. non-obese (n = 105) with the diagnosis of MASLD or MASH to examine the relationship between hepatic PAR2 expression, MASLD/MASH, and obesity. To address the direct contribution of hepatocyte PAR2 to progression of MASLD and obesity, we fed hepatocyte-specific PAR2 knockout mice, whole-body PAR2-deficient mice, and control floxed wild-type mice high-fat diet and conducted metabolic, biochemical, and molecular analyses. RESULTS: We discovered that expression of PAR2 is increased by five-to sevenfold (p = 0.002) in the livers of patients with obesity with MASLD and MASH. Hepatocyte-specific deletion of PAR2 caused reductions in body weight, liver fibrosis, and significantly lowered triglycerides and cholesterol levels in plasma and livers of mice fed high-fat diet. Global or hepatocyte-specific deletion of PAR2 resulted in significant improvements in fatty acid metabolic and reverse cholesterol transport pathways in liver. Mechanistic studies revealed that coagulation factor Xa activates a PAR2-cJun pathway that represses the HNF4α pioneer transcription factor which has global adverse effects on liver metabolism. OA-235i, a PAR2 inhibitor, enhanced HNF4α expression in livers and afforded a significant 15% reduction in weight gain (p