TY - JOUR
T1 - The selective PPAR-delta agonist seladelpar reduces ethanol-induced liver disease by restoring gut barrier function and bile acid homeostasis in mice
AU - Chu, Huikuan
AU - Jiang, Lu
AU - Gao, Bei
AU - Gautam, Nagsen
AU - Alamoudi, Jawaher A.
AU - Lang, Sonja
AU - Wang, Yanhan
AU - Duan, Yi
AU - Alnouti, Yazen
AU - Cable, Edward E.
AU - Schnabl, Bernd
N1 - Funding Information:
Conflicts of Interest: B.S. is consulting for Ferring Research Institute. This study was supported by a laboratory service agreement from CymaBay to the University of California San Diego. E.C. is an employee from CymaBay Therapeutics (Newark, CA). All authors have read the journal's authorship agreement and policy.
Funding Information:
The study was also supported by the NIDDK-funded San Diego Digestive Diseases Research Center ( P30 DK120515 ) and by the NIAAA-funded Southern California Research Center for ALPD and Cirrhosis ( P50 AA011999 ).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - Alcohol-associated liver disease is accompanied by dysregulation of bile acid metabolism and gut barrier dysfunction. Peroxisome proliferator-activated receptor-delta (PPARδ) 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 PPARδ agonism in both the liver and the intestine.
AB - Alcohol-associated liver disease is accompanied by dysregulation of bile acid metabolism and gut barrier dysfunction. Peroxisome proliferator-activated receptor-delta (PPARδ) 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 PPARδ agonism in both the liver and the intestine.
KW - Enterohepatic circulation
KW - Gut barrier
KW - Microbiome
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U2 - 10.1016/j.trsl.2020.06.006
DO - 10.1016/j.trsl.2020.06.006
M3 - Article
C2 - 32553670
AN - SCOPUS:85087366198
VL - 227
SP - 1
EP - 14
JO - Translational Research
JF - Translational Research
SN - 1931-5244
ER -