Genomic and non-genomic interactions of PPARα with xenobiotic-metabolizing enzymes

doi:10.1016/j.tem.2004.07.007

Trends in Endocrinology & Metabolism

Volume 15, Issue 7, September 2004, Pages 324-330

https://doi.org/10.1016/j.tem.2004.07.007 Get rights and content

The hypolipidemic properties of fibrates, synthetic activators of the nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), have been studied extensively. Recent observations indicate, however, that PPARα also functions as a regulator of endobiotic and xenobiotic metabolism in rodents and humans. Activators of PPARα affect xenobiotic-metabolizing enzymes (XMEs) at different levels. At the genomic level, the expression of numerous cytochrome P450 (CYP) and phase II conjugating genes is altered in a species-distinct manner on treatment with PPARα activators. As a result of such regulatory processes, PPARα affects the homeostasis of both its own natural ligands and other compounds including bile acids. At the non-genomic level, PPARα activators can act as competitive inhibitors for inactivating other molecules, leading to drug–drug interactions. These global effects of PPARα activators on the activity of XMEs are of physiological and pharmaceutical importance, and demonstrate that thorough studies of the actions on XMEs of each novel PPARα agonist are warranted.

Section snippets

The PPAR subfamily of nuclear receptors

The PPAR subfamily consists of three distinct subtypes, PPARα (also called NR1C1), PPARβ/δ (NR1C2) and PPARγ (NR1C3), that show tissue-selective expression patterns reflecting their biological functions [1]. Whereas PPARα and PPARβ/δ are expressed preferentially in tissues where fatty acids are catabolized, PPARγ is highly expressed in adipose tissue (reviewed in Ref. [2]).

Most of the physiological functions of PPARs can be explained by their activity as transcription factors that modulate the

XMEs detoxify both endobiotics and xenobiotics

The detoxification pathway for a vast variety of endogenous and exogenous molecules is composed of three distinct phases (Figure 1) [16]. The phase I reaction is catalyzed by members of the CYP superfamily 17, 18, 19. These microsomal enzymes are found in abundance in the liver, gastrointestinal tract, lung and kidney, where they catalyze oxido-reduction reactions. On the basis of amino acid sequence similarity, CYPs have been classified into more than 36 gene families. In humans, four families

Non-genomic effects of PPARα activators on XMEs

HMG-CoA reductase inhibitors (also known as statins) are cholesterol-lowering agents that are highly effective in both the primary and secondary prevention of coronary heart disease (reviewed in Ref. [63]). However, statin treatment might provoke serious, albeit rare, adverse side-effects including, first, an increase in liver enzymes, which occurs in less than 2% of treated patients 64, 65; and second, skeletal muscle dysfunctions ranging from benign myalgias to, in rare cases, fatal

Conclusion

The recent data reviewed here extend the role of PPARα not only as modulator of lipid homeostasis, but also as a crucial regulator of hepatic and extrahepatic metabolic pathways. These previously unknown functions stemming from molecular studies might give rise to novel applications of PPARα agonists, which will then have to be demonstrated in clinical practice. Furthermore, the recent application of whole-genome DNA-array technology suggests that PPARα is a more broadly regulating regulator of

Acknowledgements

This work was supported by grants from the Fondation Lefoulon-Delalande, Institut de France (to O.B.), and by; the Fonds Européen de Développement Régional (FEDER), the Conseil Régional Région Nord/Pas-de-Calais (Genopole Project #01360124) and the Leducq Foundation.

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Trends in Endocrinology & Metabolism

Genomic and non-genomic interactions of PPARα with xenobiotic-metabolizing enzymes

Section snippets

The PPAR subfamily of nuclear receptors

XMEs detoxify both endobiotics and xenobiotics

Non-genomic effects of PPARα activators on XMEs

Conclusion

Acknowledgements

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Curr. Top. Med. Chem.

PPARs: transcription factors controlling lipid and lipoprotein metabolism

Ann. New York Acad. Sci.

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation

Inflamm. Res.

The PPARs: from orphan receptors to drug discovery

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Metabolic and additional vascular effects of thiazolidinediones

Drugs

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat

Diabetes

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Bayer decides to withdraw cholesterol lowering drug

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Biochem. Pharmacol.

Regulation of cytochrome P450 (CYP) genes by nuclear receptors

Biochem. J.