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Review
, 3 (4), 354-71
eCollection

Integrated Physiology and Systems Biology of PPARα

Affiliations
Review

Integrated Physiology and Systems Biology of PPARα

Sander Kersten. Mol Metab.

Abstract

The Peroxisome Proliferator Activated Receptor alpha (PPARα) is a transcription factor that plays a major role in metabolic regulation. This review addresses the functional role of PPARα in intermediary metabolism and provides a detailed overview of metabolic genes targeted by PPARα, with a focus on liver. A distinction is made between the impact of PPARα on metabolism upon physiological, pharmacological, and nutritional activation. Low and high throughput gene expression analyses have allowed the creation of a comprehensive map illustrating the role of PPARα as master regulator of lipid metabolism via regulation of numerous genes. The map puts PPARα at the center of a regulatory hub impacting fatty acid uptake, fatty acid activation, intracellular fatty acid binding, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, lipid droplet biology, gluconeogenesis, and bile synthesis/secretion. In addition, PPARα governs the expression of several secreted proteins that exert local and endocrine functions.

Keywords: Expression profiling; Lipid metabolism; Liver; Metabolic homeostasis; PPARα; Systems biology; Transcriptional networks.

Figures

Figure 1
Figure 1
Overall role of PPARα in the adaptive response to fasting. Fasting is associated with activation of adipose tissue lipolysis, leading to the release of free fatty acids and glycerol into the circulation. Free fatty acids taken up by the liver are partially oxidized and converted into ketone bodies, or completely oxidized to CO2. Glycerol is converted into glucose, as are amino acids coming from skeletal muscle. The processes induced by PPARα are indicated by green arrows. The processes suppressed by PPARα are indicated by red arrow. TG = triglycerides, FA = fatty acids, KB = ketone bodies, AA = amino acids.
Figure 2
Figure 2
Role of PPARα in hepatic lipid metabolism. Free fatty acids released by adipose tissue lipolysis are taken up by hepatocytes and either converted into triglycerides or, after conversion to acyl-carnitine, are oxidized in the mitochondria. The metabolic steps or pathways under transcriptional control of PPARα are indicated in red. A) The normal situation in fasted wildtype mice. B) Consequences of PPARα deletion on metabolic pathways and specific intra- and extracellular metabolites in the fasted state.
Figure 3
Figure 3
Detailed overview map of metabolic genes upregulated by PPARα in mouse liver. The map is based on the published literature combined with transcriptomics analysis of liver of wildtype and PPARα−/− mice. Colors indicate whether expression of a gene is governed by PPARα during fasting (In green: significantly decreased expression in fasted PPARα−/− mice compared with fasted wildtype mice, representing physiological regulation), and/or by synthetic PPARα agonists (In blue: significantly increased expression in wildtype mice treated with Wy14643 or fenofibrate compared with vehicle-treated wildtype mice, representing pharmacological/toxicological regulation). Genes shown in red are upregulated by PPARα during fasting and are upregulated by Wy14643/fenofibrate. Genes were excluded if they were only upregulated upon chronic administration of Wy14643/fenofibrate, which likely reflects indirect regulation. Genes in this category included Mecr, Fads1, and Lpl.
Figure 4
Figure 4
Pathways upregulated by PPARα during fasting or by Wy14643. Gene set enrichment analysis was performed on transcriptomics data comparing livers from 24 h fasted PPARα+/+ and 24 h fasted PPARα−/− mice (A), or livers from wildtype mice treated with Wy14643 or treated with vehicle for 5 days (B). The top 20 most significant positively enriched (upregulated) gene sets are shown ranked according to normalized enrichment score.
Figure 5
Figure 5
Detailed overview map of metabolic genes upregulated by PPARα in human hepatocytes. The map is based on the published literature, including transcriptomics analysis of primary human hepatocytes treated with synthetic PPARα agonists.

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