Insights into the Role of PPARβ/δ in NAFLD

Figures

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  Figure 1. Schematic diagram of the two-hit hypothesis of non-alcoholic fatty liver disease (NAFLD) progression. In the first hit, an imbalance of lipid synthesis, catabolism, and export results in lipid accumulation in liver (steatosis). Obesity and insulin resistance are strongly correlated with liver steatosis. In the second hit, further inflammation processes lead to non-alcoholic steatohepatitis (NASH) and fibrosis, which can evolve into more severe stages, such as cirrhosis and ultimately hepatocellular carcinoma.

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  Figure 2. Schematic illustration of the multiple parallel hits hypothesis of NAFLD development. NAFLD develops due to the impaired regulation of several factors, such as gut nutrient-derived signals, adipokines, and certain pro-inflammatory cytokines.

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  Figure 3. Regulatory mechanisms of gene transcription by peroxisome proliferator-activated receptors (PPARs). Each PPAR structurally comprises an N-terminal domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LBD). In the absence of a ligand or in the presence of an antagonist, the PPAR-RXR heterodimer associates with nuclear receptor co-repressor proteins, leading to repression of PPAR target genes (Repression). Fatty acid-binding protein (FABP) associates with the ligand/agonist to transport it into the cell. Upon ligand binding, a conformational change in PPAR leads to co-repressor dissociation, and co-activators are recruited. The activated PPAR-RXR heterodimer binds the peroxisome proliferator response element (PPRE) and stimulates target gene transcription (Transactivation). In macrophages, endothelial cells, and vascular smooth muscles, in the absence of a PPARβ/δ agonist or ligand, the receptor will scavenge BCL-6 (a PPARβ/δ-associated transcriptional repressor). Once PPARβ/δ neutralizes BCL-6, transcription factors (TFs) bind to TF-binding sites (TFBSs), allows transcription of the genes repressed by BCL-6. However, the binding of a PPARβ/δ ligand to PPARβ/δ…

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  Figure 4. Overview of research findings regarding PPARβ/δ in hepatic metabolism, and the contrasting effects of various PPARβ/δ agonist treatments in pre-clinical models.