Novel aspects of PPARα-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study

✍ Scribed by Pascal G. P. Martin; Hervé Guillou; Frédéric Lasserre; Sébastien Déjean; Annaig Lan; Jean-Marc Pascussi; Magali SanCristobal; Philippe Legrand; Philippe Besse; Thierry Pineau

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 705 KB
• Volume: 45
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21510

✦ Synopsis

Peroxisome proliferator-activated receptor-␣ (PPAR␣) is a major transcriptional regulator of lipid metabolism. It is activated by diverse chemicals such as fatty acids (FAs) and regulates the expression of numerous genes in organs displaying high FA catabolic rates, including the liver. The role of this nuclear receptor as a sensor of whole dietary fat intake has been inferred, mostly from high-fat diet studies. To delineate its function under low fat intake conditions (4.8% w/w), we studied the effects of five regimens with contrasted FA compositions on liver lipids and hepatic gene expression in wild-type and PPAR␣-deficient mice. Diets containing polyunsaturated FAs reduced hepatic fat stores in wild-type mice. Only sunflower, linseed, and fish oil diets lowered hepatic lipid stores in PPAR␣ ؊/؊ mice, a model of progressive hepatic triglyceride accumulation. These beneficial effects were associated, in particular, with dietary regulation of ⌬9-desaturase in both genotypes, and with a newly identified PPAR␣-dependent regulation of lipin. Furthermore, hepatic levels of 18-carbon essential FAs (C18:26 and C18:33) were elevated in PPAR␣ ؊/؊ mice, possibly due to the observed reduction in expression of the ⌬6-desaturase and of enoylcoenzyme A isomerases. Effects of diet and genotype were also observed on the xenobiotic metabolism-related genes Cyp3a11 and CAR. Conclusion: Together, our results suggest that dietary FAs represent-even under low fat intake conditions-a beneficial strategy to reduce hepatic steatosis. Under such conditions, we established the role of PPAR␣ as a dietary FA sensor and highlighted its importance in regulating hepatic FA content and composition. (HEPATOLOGY 2007;45:767-777.) T he nuclear receptor (NR) superfamily in the mouse is composed of 49 transcriptional regulators of gene expression that respond to a wide variety of small lipophilic molecules. The NRs are impli-cated in numerous biological processes, including development, cell proliferation and differentiation, inflammation, energy, and xenobiotic metabolism. Among them, the peroxisome proliferator-activated receptors (PPAR␣, ␤/␦, and ␥ or NR1C1, C2 and C3) are important modulators of lipid metabolism. In organs displaying high fatty acid (FA) catabolic rates, PPAR␣ regulates the expression of genes involved in most aspects of FA catabolism (FA uptake, activation, trafficking, ␣and ␤-oxidation, -hydroxylation, ketogenesis), polyunsaturated FA (PUFA) biosynthesis (elongation and desaturation), and lipoprotein metabolism (apolipoprotein C-III, lipoprotein lipase). PPAR␣ also plays important roles in inflammation, glucose and bile and amino acid metabolism, biotransformations, and hepatocarcinogenesis (reviewed by Mandard et al. 1 ).

PPAR␣ is activated by structurally diverse molecules known as peroxisome proliferators, which induce hepatic peroxisome proliferation and modulate the expression of several target genes in rodents. 2 Among the peroxisome proliferators, fibrates are potent hypolipidemic drugs beneficially administered to humans. In vitro, several FAs bind to and activate PPAR␣ at physiologically relevant concentrations. 3 In vivo, high-fat (24% w/w) 4 and fish oil (10% w/w) 5 diets activate PPAR␣. Thus, activation of