Coffee peel polyphenols ameliorate nonalcoholic fatty liver disease by modulating cannabinoid receptor type‐1‐ceramide axis

Cannabinoid receptor type-1 (CB1) signaling plays an important part in maintenance of energy homeostasis, and CB1 blockers have shown promise in the treatment of obesity-related metabolic dysfunction. Coffee peel contains abundant phytochemicals and possesses hypolipidemic and anti-inflammatory activities. The present study aimed to elucidate the preventive effect of coffee peel polyphenols (CPPs) on nonalcoholic fatty liver disease (NAFLD) from the perspective of CB1 signaling. Male C57BL/6J mice were fed a high-fat and high-cholesterol diet and CPPs (200/400 mg/kg/day) for 8 weeks. Serum biochemical indexes and liver pathological analysis were used to evaluate the effect of CPPs on NAFLD. Untargeted/targeted lipidomics analyses were used to evaluate the levels of endocannabinoid ligands and ceramides in serum and liver. The expression levels of proteins were detected by using Western blotting analysis. Administration of CPPs significantly improved hepatic steatosis, insulin resistance and biomarkers of liver function. Meanwhile, CPPs administration indicated reductions in endocannabinoid ligands, including anandamide and 2-arachidonoylglycerol levels, associated with blockade of CB1 overexpression. Blockage of CB1 signaling depleted hepatic C16:0- and C18:0-ceramide concentrations by enhancing ceramide metabolism. The reductions in hepatic ceramide concentrations contributed to down-regulating sterol regulatory element-binding protein-1c and up-regulating proliferator activated receptor alpha, leading to decrease de novo lipogenesis and increase fatty acid β-oxidation in the liver, respectively. This study demonstrated a novel mechanism that CPPs could ameliorate NAFLD through modulating CB1-ceramide axis.