Lipid Metabolism Modulation via Peroxisome Proliferator-Activated Receptor α

Peroxisome Proliferator-Activated Receptor α (PPARα) is a ligand-activated nuclear receptor that functions as a master regulator of lipid metabolism. Expressed predominantly in oxidative tissues such as the liver, heart and skeletal muscle, PPARα senses fatty acid derivatives and orchestrates transcriptional programmes governing fatty acid uptake, peroxisomal and mitochondrial β-oxidation, ketogenesis and bile acid synthesis. Through heterodimerisation with retinoid X receptor α and binding to Peroxisome Proliferator Response Elements, PPARα modulates sets of genes that adapt energy homeostasis to nutritional states, particularly during fasting or high-fat feeding. Pharmacological activators, including fibrates and certain bile acids, exploit PPARα pathways to ameliorate dyslipidaemia, steatosis and inflammation. Emerging insights into nuclear-cytoplasmic shuttling, zonal heterogeneity and co-regulator interactions expand our understanding of how PPARα modulation can be harnessed for therapies against nonalcoholic fatty liver disease, steatohepatitis and cardiometabolic disorders.

Research from Nature Portfolio

Recent studies have identified hyodeoxycholic acid (HDCA) as a naturally occurring bile acid that reverses hepatic steatosis by promoting PPARα nuclear retention. In models of nonalcoholic fatty liver disease, dietary HDCA levels decline, correlating with disease severity. Supplementation restores HDCA concentrations, directly interacts with the RAN protein to disrupt its complex with CRM1 and PPARα, and enhances PPARα-dependent fatty acid oxidation. The antisteatotic effect of HDCA is abolished in hepatocyte-specific PPARα knockout mice, underlining the central role of nuclear receptor signalling in bile acid-mediated lipid homeostasis and offering a novel therapeutic avenue.

Lipid Metabolism Modulation via Peroxisome Proliferator-Activated Receptor α publication trend

The graph below shows the total number of articles in lipid metabolism modulation via peroxisome proliferator-activated receptor α across all publications each year (not limited to Nature Index journals).

Technical terms

Peroxisome Proliferator-Activated Receptor α (PPARα): Ligand-activated nuclear receptor that regulates genes involved in lipid uptake, oxidation and energy homeostasis.

Peroxisome: Membrane-bound organelle where very-long-chain fatty acids undergo initial β-oxidation.

β-Oxidation: Metabolic pathway in peroxisomes and mitochondria that sequentially cleaves fatty acids to generate acetyl-CoA.

Bile acids: Amphipathic molecules derived from cholesterol that facilitate dietary lipid absorption and act as signalling regulators of metabolic pathways.

References

1. Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. Journal of Hepatology (2024).
2. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1. Cell Metabolism (2024).
3. Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling. Nature Communications (2023).
4. Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting. Progress in Lipid Research (2024).