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 <0.0001), and improvements in systemic and liver lipid and cholesterol levels in obese mouse models.

CONCLUSIONS: These data provide support that targeting hepatic PAR2 may potentially provide broad liver and cardiometabolic benefits to patients with MASLD and MASH.

IMPACT AND IMPLICATIONS: Dyslipidemia and heightened coagulation are closely linked with poor cardiometabolic outcomes in patients with fatty liver disease, but the connection with progression of MASLD to steatohepatitis (MASH) is complex and not well understood. In this study, the authors now link the factor Xa coagulation protease receptor PAR2 with obesity and dyslipidemia and showed that hepatic PAR2 expression is significantly elevated in patients who are overweight or obese with MASLD and MASH compared with non-obese controls. A liver-homing PAR2 pepducin, OA-235i, conferred significantly lower body weight gain with major improvements in liver histology, fibrosis, and cholesterol and triglyceride levels in mice with MASLD. The translational studies presented here support additional investigation to determine whether a PAR2 inhibitor represents a new therapeutic strategy to treat patients with severe metabolic diseases such as MASLD and MASH.