Co-option of PPARα in the regulation of lipogenesis and fatty acid oxidation in CLA-induced hepatic steatosis

Nonalcoholic-fatty-liver-disease (NAFLD) is the result of imbalances in hepatic lipid partitioning and is linked to dietary factors. We demonstrate that conjugated linoleic acid (CLA) when given to mice as a dietary supplement, induced an enlarged liver, hepatic steatosis, and increased plasma levels of fatty acid (FA), alanine transaminase, and triglycerides. The progression of NAFLD and insulin resistance was reversed by GW6471 a small-molecule antagonist of peroxisome proliferator-activated receptor alpha (PPAR alpha). Transcriptional profiling of livers revealed that the genes involved in FA oxidation and lipogenesis as two core gene programs controlled by PPAR alpha in response to CLA and GW6471 including Acaca and Acads. Bioinformatic analysis of PPAR alpha ChIP-seq data set and ChIP-qPCR showed that GW6471 blocks PPAR alpha binding to Acaca and Acads and abolishes the PPAR alpha-mediated local histone modifications of H3K27ac and H3K4me1 in CLA-treated hepatocytes. Thus, our findings reveal a dual role of PPAR alpha in the regulation of lipid homeostasis and highlight its druggable nature in NAFLD.

Automated summary

The study demonstrates that conjugated linoleic acid (CLA) can induce liver abnormalities in mice, while a PPARα antagonist called GW6471 can reverse the progression of NAFLD and insulin resistance by controlling gene expression related to fatty acid oxidation and synthesis. This highlights the potential druggable nature of PPARα in regulating lipid homeostasis in NAFLD.