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

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.