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The Role of PPARα in Fatty Acid Metabolism and Hepatocarcinogenesis: Studies with PPARα-Null Mice

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Peroxisome Proliferator Activated Receptors: From Basic Science to Clinical Applications

Part of the book series: Medical Science Symposia Series ((MSSS,volume 18))

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Abstract

A clofibrate inducible P450 that carries out the ω and ω-1 oxidation of fatty acids was purified from liver [1,2] and antibody derived from the purified protein was used to isolate a cDNA [1]. The “clofibrate-inducible” rat P450 was later named CYP4A1 based on the nomenclature system developed for the P450 superfamily (http://drnelson.utmem.edu/CytochromeP450.html). Two additional members of the CYP4A family were found in rats [3,4]. The CYP4A1 was the first member of a subfamily of P450s that oxidize a number of endogenous and exogenous fatty acids. Treatment of rats with clofibrate results in a rapid induction of CYP4A1 gene transcription and mRNA [2]. The mechanism of induction by clofibrate remained elusive until the discovery of the peroxisome proliferator-activated receptor (PPAR) in 1990 [5,6]. This receptor, subsequently named PPARα, is one of three members of a family in the nuclear receptor superfamily. The CYP4A1 gene was found to possess a functional binding site for PPARα [7]. Two additional members of the PPAR family were subsequently discovered and named PPARβ(δ) and PPARγ [8,9]. Only PPARα is able to induce transcription of the CYP4A P450s in liver and kidney of species that are responsive to peroxisome proliferators. The PPARs are representative of a group of nuclear receptors that require retinoid X receptor (RXR) as an obligate heterodimeric partner for activity [10].

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Authors
  1. Frank J. Gonzalez
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Editor information

Editors and Affiliations

  1. Faculté des Sciences Pharmaceutiques et Biologiques, Inserm U 545, Dept. Atherosclerose, Institut Pasteur de Lille, Université de Lille II, Lille, France

    J.-C. Fruchart

  2. Weill Medical College of Cornell University, New York, New York, USA

    A. M. Gotto Jr.

  3. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    R. Paoletti  & A. L. Catapano  & 

  4. Department of Atherosclerosis, Pasteur Institute, Inserm U 545, University of Lille II, Lille, France

    B. Staels

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Gonzalez, F.J. (2002). The Role of PPARα in Fatty Acid Metabolism and Hepatocarcinogenesis: Studies with PPARα-Null Mice. In: Fruchart, JC., Gotto, A.M., Paoletti, R., Staels, B., Catapano, A.L. (eds) Peroxisome Proliferator Activated Receptors: From Basic Science to Clinical Applications. Medical Science Symposia Series, vol 18. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1171-7_9

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  • DOI: https://doi.org/10.1007/978-1-4615-1171-7_9

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5427-7

  • Online ISBN: 978-1-4615-1171-7

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