期刊
TRANSLATIONAL RESEARCH
卷 227, 期 -, 页码 1-14出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.trsl.2020.06.006
关键词
Gut barrier; Enterohepatic circulation; Microbiome
资金
- NIDDK-funded San Diego Digestive Diseases Research Center [P30 DK120515]
- NIAAA-funded Southern California Research Center for ALPD [P50 AA011999]
The study demonstrates that the selective PPAR-delta agonist Seladelpar (MBX-8025) can prevent and treat ethanol-induced liver damage in mice by directly acting on PPAR delta in both the liver and the intestine. MBX-8025 effectively protects mice from ethanol-induced liver disease, restores ethanol-induced gut dysbiosis and gut barrier dysfunction.
Alcohol-associated liver disease is accompanied by dysregulation of bile acid metabolism and gut barrier dysfunction. Peroxisome proliferator-activated receptor-delta (PPAR delta) agonists are key metabolic regulators and have anti-inflammatory properties. Here, we evaluated the effect of the selective PPAR-delta agonist seladelpar (MBX-8025) on gut barrier function and bile acid metabolism in a mouse model of ethanol-induced liver disease. Wild type C57BL/6 mice were fed LieberDeCarli diet containing 0%-36% ethanol (caloric) for 8 weeks followed by a single binge of ethanol (5 g/kg). Pair fed mice received an isocaloric liquid diet as control. MBX-8025 (10 mg/kg/d) or vehicle were added to the liquid diet during the entire feeding period (prevention), or during the last 4 weeks of Lieber DeCarli diet feeding (intervention). In both prevention and intervention trials, MBX-8025 protected mice from ethanol-induced liver disease, characterized by lower serum alanine aminotransferase (ALT) levels, hepatic triglycerides, and inflammation. Chronic ethanol intake disrupted bile acid metabolism by increasing the total bile acid pool and serum bile acids. MBX-8025 reduced serum total and secondary bile acids, and the total bile acid pool as compared with vehicle treatment in both prevention and intervention trials. MBX-8025 restored ethanol-induced gut dysbiosis and gut barrier dysfunction. Data from this study demonstrates that seladelpar prevents and treats ethanol-induced liver damage in mice by direct PPAR delta agonism in both the liver and the intestine.
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