Coagulation protease-activated receptor-2 (PAR2) promotes dyslipidemia, obesity and MASLD through suppression of a hepatic pioneer factor HNF4a

MASLD and its more severe version, MASH, are attributable to metabolic dysfunction and are associated with cardiometabolic disease, atherothrombosis, and obesity. The exact pathophysiological mechanisms linking MASLD and CVD have yet to be elucidated but share common metabolic abnormalities that could interact synergistically to increase the risk of both heart disease and liver disease. Protease-activated receptor 2 (PAR2), a receptor activated by prothrombotic coagulation proteases that are dysregulated in inflammatory and fibrotic diseases, is emerging as a new drug target for MASH. Using patient samples, we discovered that expression of liver PAR2 is increased in the livers of obese patients with MASLD and MASH.To address the direct contribution of hepatocyte PAR2 to progression of MASLD and obesity, we fed hepatocyte-specific PAR2 knockout mice(PAR2dHep), whole-body PAR2-deficient mice(PAR2 KO), and control floxed WT mice(PAR2fl/fl) high-fat diet and conducted metabolic, biochemical and RNA-seq analyses. Hepatocyte-specific deletion of PAR2 caused a reduction in body weight and significantly lowered triglycerides and cholesterol levels in plasma and livers of mice fed high-fat diet. Analysis of bulk liver RNA seq data showed that global or hepatocyte-specific deletion of PAR2 resulted in significant improvements in fatty acid metabolic and reverse cholesterol transport pathways in liver.These data provide support that targeting hepatic PAR2 may potentially provide broad liver and cardiometabolic benefits to patients with MASLD and MASH.