Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

Hepatology. 2020 May;71(5):1750-1765. doi: 10.1002/hep.30929. Epub 2019 Dec 30.

Abstract

Background and aims: Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors 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, a disease so far lacking effective pharmacological therapy.

Approach and results: To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL-/- ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2-/- ) mouse model of sclerosing cholangitis. 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 and increased FA/BA metabolism and β-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2-/- mice 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 and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation.

Conclusions: Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP-Binding Cassette Sub-Family B Member 4
  • Animals
  • Benzodioxoles / therapeutic use*
  • Bile Acids and Salts / metabolism
  • Caco-2 Cells
  • Cholangitis, Sclerosing / complications
  • Cholangitis, Sclerosing / drug therapy*
  • Cholestasis / complications
  • Cholestasis / drug therapy*
  • Disease Models, Animal
  • Enzyme Inhibitors / therapeutic use*
  • Fatty Acids / metabolism
  • Humans
  • Liver Cirrhosis, Biliary / etiology
  • Liver Cirrhosis, Biliary / prevention & control*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Piperidines / therapeutic use*
  • Pyridines / toxicity

Substances

  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • ATP Binding Cassette Transporter, Subfamily B
  • Benzodioxoles
  • Bile Acids and Salts
  • Enzyme Inhibitors
  • Fatty Acids
  • JZL 184
  • Piperidines
  • Pyridines
  • Monoacylglycerol Lipases