Peroxisome Proliferator-Activated Receptor Dynamics in Liver Metabolism

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear receptors that serve as master regulators of hepatic energy homeostasis, lipid handling and inflammatory responses. Three PPAR isotypes—PPARα, PPARβ/δ and PPARγ—exhibit distinct yet overlapping functions in the liver. PPARα predominates in hepatocytes under fasting conditions, orchestrating fatty acid uptake, peroxisomal and mitochondrial β-oxidation, and very low-density lipoprotein (VLDL) assembly to prevent steatosis. PPARβ/δ supports balanced lipid and glucose metabolism during both feeding and fasting, modulating pathways that govern de novo lipogenesis, glycolysis and insulin sensitivity, while also attenuating pro-inflammatory signalling in resident macrophages. PPARγ is expressed at lower basal levels in hepatocytes but becomes upregulated in steatotic or inflamed liver, where it drives lipogenic gene programmes and can influence fibrosis through cross-talk with hepatic stellate cells. Dynamic regulation of PPAR activity involves selective ligand binding, cofactor recruitment, post-translational modifications and interplay with other nuclear receptors, enabling rapid adaptation to nutrient fluctuations. Dysregulation of PPAR signalling is implicated in non‐alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH) and progression to cirrhosis or carcinoma. A growing repertoire of synthetic and natural PPAR agonists—ranging from isoform-selective modulators to dual and pan-PPAR ligands—has demonstrated efficacy in preclinical models and clinical trials, highlighting the therapeutic promise of fine-tuning receptor dynamics to restore metabolic balance and curb inflammation in liver disease.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Peroxisome Proliferator-Activated Receptor Dynamics in Liver Metabolism publication trend

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

Technical terms

Peroxisome proliferator-activated receptor (PPAR): Ligand-activated nuclear receptor that regulates gene expression involved in lipid metabolism, glucose homeostasis and inflammation.

Hepatocyte: Liver parenchymal cell responsible for metabolic functions including detoxification, protein synthesis and lipid processing.

Ligand-binding domain: Region of a nuclear receptor that recognises and binds specific small-molecule activators or inhibitors.

Steatohepatitis: Liver condition characterised by fat accumulation (steatosis) coupled with inflammation and hepatocyte injury.

References

1. Herpetrione, a New Type of PPARα Ligand as a Therapeutic Strategy Against Nonalcoholic Steatohepatitis. Research (2023).
2. Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ. Biomedicine & Pharmacotherapy (2023).
3. PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice. International Journal of Molecular Sciences (2020).
4. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells (2020).
5. Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences (2022).