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Κυριακή 15 Νοεμβρίου 2020

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

Alexandros G.Sfakianakis shared this article with you from Inoreader
Co‐option of PPARα in the regulation of lipogenesis and fatty acid oxidation in CLA‐induced hepatic steatosis

1.

Hepatic PPARα is responsible for dietary CLA‐induced NAFLD and insulin resistance in mice.

2.

PPARα activation co‐opts lipogenesis and FA oxidation gene programs in hepatic steatosis. However, PPARα inhibition blocks the enrichment of active histone marks H3K27ac and H3K4me1 and cofactors on the target locus.

3.

GW6471 exploits PPARα as a therapeutic target by reprograming genes key to lipid homeostasis (e.g., Acaca and Acads), and confers protection against NAFLD.


Abstract

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 α (PPARα). Transcriptional profiling of livers revealed that the genes involved in FA oxidation and lipogenesis as two core gene programs controlled by PPARα in response to CLA and GW6471 including Acaca and Acads. Bioinformatic analysis of PPARα ChIP‐seq data set and ChIP‐qPCR showed that GW6471 blocks PPARα binding to Acaca and Acads and abolishes the PPARα‐mediated local histone modifications of H3K27ac and H3K4me1 in CL A‐treated hepatocytes. Thus, our findings reveal a dual role of PPARα in the regulation of lipid homeostasis and highlight its druggable nature in NAFLD.

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