Integrated physiology and systems biology of PPARα

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.

E4BP4 is an insulin-induced stabilizer of nuclear SREBP-1c and promotes SREBP-1c-mediated lipogenesis

“…E4bp4 depletion also showed a modest effect on a subset of genes of fatty acid oxidation (Acox1 and Cpt1a) (Fig. 3G, right panel) (53). In summary, our data illustrate a crucial and selective role of E4BP4 in activating the hepatic lipogenesis program during the postprandial phase.…”

Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

“…6C). Increased expression of Ppar and Sirt1 by Western diet may reduce liver triglyceride content and increase fecal fatty acid secretion in Cyp7a1 / mice (27,28). Lastly, we measured the expression of energy metabolism genes in brown adipose tissue, and found no significant changes in the expression in Ppar coactivator 1 (Pgc1), Ppar, Sirt1, or uncoupling protein (Ucp), supporting our data that the phenotype demonstrated in Cyp7a1 / mice is not due to changes in energy metabolism (supplementary Fig.…”

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

“…Importantly, these genes were also induced by fenofibric acid treatment. In addition, nine of these 11 genes (except for AADAC and SLC25A42) have been reported to be direct PPAR target genes [11][12][13][14][15][16] . Arylacetamide deacetylase (AADAC) and SLC25A42 are involved in VLDL assembly 17) and coenzyme A transport 18) , respectively, and are important for determining the fatty acid fate.…”