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Hepatology ; 71(5): 1750-1765, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31505038

RESUMEN

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 ß-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.


Asunto(s)
Benzodioxoles/uso terapéutico , Colangitis Esclerosante/tratamiento farmacológico , Colestasis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Cirrosis Hepática Biliar/prevención & control , Monoacilglicerol Lipasas/antagonistas & inhibidores , Piperidinas/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Ácidos y Sales Biliares/metabolismo , Células CACO-2 , Colangitis Esclerosante/complicaciones , Colestasis/complicaciones , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Humanos , Cirrosis Hepática Biliar/etiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Piridinas/toxicidad , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
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