Monoacylglycerol lipase inhibition protects from liver injury in mouse models of sclerosing cholangitis.
キーワード
概要
Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FA) and converting 2-arachidonoylglycerol into arachidonic acid (AA), thus providing ligands for nuclear receptors (NRs) as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis (SC), a disease so far lacking effective pharmacological therapy. To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce SC in wild type (WT) and knockout (MGL-/- ) mice and tested pharmacological inhibition with JZL184 in the Mdr2-/- mouse model of SC. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL-/- mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes, increased FA/BA metabolism and β-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2-/- from spontaneous liver injury, with improved liver enzymes, inflammation and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E2 accumulation in the intestine upregulating peroxisome proliferator activated receptor (PPAR) -α and -γ activity, thus reducing inflammation. Conclusions: Collectively, our study unravels MGL as a novel metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for SC.