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Biochemical and Molecular Actions of Nutrients

Fatty Acids Induce L-CPT I Gene Expression through a PPAR-Independent Mechanism in Rat Hepatoma Cells

Institut Cochin, INSERM U567, CNRS UMR 8104, Université PARIS V, Département d’Endocrinologie, 24 rue du Faubourg St Jacques, 75014 Paris

¹To whom correspondence should be addressed. E-mail: pegorier{at}cochin.inserm.fr.

Liver carnitine palmitoyl transferase (L-CPT) I is a key regulatory enzyme of long-chain fatty acid (LCFA) oxidation that ensures the first step of LCFA import into the mitochondrial matrix. In rat hepatocytes, we showed previously that L-CPT I gene expression was induced by LCFAs as well as by fibrates. The aim of this study was to determine whether LCFA-induced L-CPT I gene expression was mediated by PPAR. For this purpose, we constructed a PPAR-dominant negative receptor to inhibit endogenous PPAR signaling. Highly conserved hydrophobic and charged residues (Leu⁴⁵⁹ and Glu⁴⁶²) in helix 12 of the ligand-binding domain were mutated to alanine. These mutations led to a total loss of transcriptional activity due to impaired coactivator recruitment. Furthermore, competition studies confirmed that the mutated PPAR receptor abolished the wild-type PPAR receptor action and thus acted as a powerful dominant negative receptor. When overexpressed in rat hepatoma cells (H4IIE) using a recombinant adenovirus, the mutated PPAR receptor antagonized the clofibrate-induced L-CPT I gene expression, whereas it did not affect LCFA-induced L-CPT I. These results provide the first direct demonstration that LCFAs regulate L-CPT I transcription through a PPAR-independent pathway, at least in hepatoma cells.

KEY WORDS: • dominant negative PPAR • recombinant adenovirus • carnitine palmitoyl transferase I • hepatoma cell • fatty acid–induced gene expression

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