Peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-driven lipid metabolism pathway (PPAR/SREBP pathway)

The PPAR/SREBP-driven lipid metabolism pathway represents a fundamental regulatory axis that maintains cellular and systemic lipid homeostasis [1, 3]. Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated nuclear receptors that primarily enhance fatty acid oxidation, lipid transport, and insulin sensitivity [1, 5]. In contrast, Sterol Regulatory Element-Binding Proteins (SREBPs) are master transcription factors that upregulate the expression of genes involved in the de novo synthesis of fatty acids, triglycerides, and cholesterol [2, 4]. The reciprocal regulation and crosstalk between these pathways ensure that lipid availability matches metabolic demand, preventing the accumulation of lipotoxic intermediates [3]. Dysregulation of this network is a central driver in the development of metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes [3, 5]. Pharmacological interventions targeting these pathways, such as PPAR agonists (e.g., fibrates and thiazolidinediones) and experimental SREBP inhibitors, aim to correct metabolic imbalances and reduce cardiovascular risk [4, 6]. However, therapeutic development is often hindered by systemic side effects, including weight gain, fluid retention, and potential hepatotoxicity, necessitating the development of more selective modulators [1, 6]. References: [1] StatPearls, PPARs (https://www.ncbi.nlm.nih.gov/books/NBK559218/); [2] UniProt, SREBP (https://www.uniprot.org/uniprotkb/P36956/entry); [3] Journal of Lipid Research, PPAR/SREBP crosstalk (https://www.jlr.org/article/S0022-2275(20)30123-X/fulltext); [4] PubMed, SREBP targeting (https://pubmed.ncbi.nlm.nih.gov/30232304/); [5] Nature Reviews Drug Discovery, PPAR agonists (https://www.nature.com/articles/nrd2675); [6] Diabetes Care, PPAR safety (https://care.diabetesjournals.org/content/30/6/1506).

Other names

PPAR-SREBP axisPPAR/SREBP signaling networkLipid metabolism regulatory pathwayPPAR-SREBP transcriptional network

Modulation of gene expression involved in lipid synthesis and oxidation through the activation of PPAR nuclear receptors or the inhibition of SREBP transcription factor processing [1, 4].