Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming

Background & Aims: Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it. Methods: A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPAR alpha, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro. Results: We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPAR alpha-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPAR alpha inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPAR alpha and SREBP2 to the genomic DNA response element. We showed that NR ROR gamma functions as an essential mediator that facilitates the interaction of PPAR alpha and SREBP2 to modulate the cholesterol biosynthesis genes expression. Conclusions: Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the PPAR alpha-ROR gamma-SREBP2 being a potential complex player in this hepatic cholesterol biosynthesis programming.

Automated summary

This study revealed that dietary conjugated linoleic acids (CLA) can induce hypercholesterolemia (HCL) and liver steatosis through multiple pathways, with PPAR alpha, ROR gamma, and SREBP2 being important players in the hepatic cholesterol biosynthesis programming. The small-molecule compound GW6471 was found to have a therapeutic effect for CLA-induced HCL by disrupting the physical association between PPAR alpha and SREBP2, thus affecting the expression of cholesterol biosynthesis genes.