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Purpose   Peroxisome proliferator-activated receptor  α  (PPAR α ) plays a crucial role in the control of lipid homeostasis. Here, we investigated the effects of CP775146, a new selective PPAR α  agonist, on lipid metabolism in diet-induced obese mice and its possible mechanism.Methods   C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and then received CP775146 via intraperitoneal injection for 3 days. The content/morphology of the liver, serum lipid, and liver function was measured. The expression of genes related to lipolysis and synthesis in liver was detected by quantitative real-time PCR (qRT-PCR).Results   The safe dose of CP775146 was <0.3 mg/kg. CP775146 reduced the serum levels of liver enzymes, such as alanine aminotransferase (ALT) and glutamic-oxaloacetic transaminase (AST) and lipid metabolism-related biomarkers, including triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein cholesterol (non-HDL-c), and hepatic TG content, at a dosage of 0.1 mg/kg. HFD-induced pathological liver changes improved after CP775146 treatment. The expression of genes involved in liver fatty acid oxidation (acyl-coenzyme A dehydrogenase, long chain ( Acadl ), acyl-CoA oxidase 1 ( Acox - 1 ), carnitine palmitoyltransferase-1 ( CPT - 1 ), and enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase ( Ehhadh )) was upregulated in CP775146-treated mice. Furthermore, CP775146 induced the expression of thermogenesis genes (cell death-inducing DFFA-like effector a ( Cidea ), uncoupling protein 1 ( Ucp1 )) and lipolysis genes (hormone-sensitive lipase ( Hsl ), adipose tissue triglyceride lipase ( Atgl )) in epididymal white adipose tissue (eWAT), activating browning and thermogenesis.Conclusion   CP775146 efficiently alleviates obesity-induced liver damage, prevents lipid accumulation by activating the liver fatty acid  β -oxidation pathway, and regulates the expression of genes that control brown fat-like pathway in eWAT.

The Effects of New Selective PPARα Agonist CP775146 on Systematic Lipid Metabolism in Obese Mice and Its Potential Mechanism