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Published on: April 16, 2019
Chiglitazar attenuates high-fat diet-induced nonalcoholic fatty liver disease by modulating multiple pathways in mice
Lijuan Liu1, Weiming Sun2, Xulei Tang1
1Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways.
Insights
Chiglitazar, a pan-PPAR agonist, shows therapeutic potential for nonalcoholic fatty liver disease (NAFLD). It improved metabolic health, reduced liver fat, inflammation, and oxidative stress in NAFLD mice.
Area of Science:
- Hepatology
- Metabolic Diseases
- Pharmacology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a prevalent global liver condition with limited effective treatments.
- Developing novel therapeutic strategies for NAFLD is a critical unmet medical need.
Purpose of the Study:
- To evaluate the efficacy of chiglitazar, a pan-PPAR agonist, in a mouse model of NAFLD.
- To elucidate the molecular mechanisms underlying chiglitazar's protective effects against NAFLD.
Main Methods:
- Male C57BL/6J mice were induced with NAFLD via a high-fat diet (HFD).
- Mice received varying doses of chiglitazar (5 or 10 mg/kg/d) or vehicle via gavage for 10 weeks.
- RNA sequencing (RNA-seq) was employed to analyze molecular pathways affected by chiglitazar.
Main Results:
- Chiglitazar treatment significantly improved dyslipidemia and insulin resistance in NAFLD mice.
- The drug ameliorated hepatic steatosis, reduced liver inflammation, and decreased oxidative stress.
- RNA-seq analysis indicated chiglitazar modulates fatty acid metabolism, insulin signaling, and AMPK signaling pathways.
Conclusions:
- Chiglitazar demonstrates significant therapeutic potential for ameliorating nonalcoholic fatty liver disease.
- The compound exerts its protective effects by modulating multiple key molecular pathways involved in NAFLD pathogenesis.
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