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Regulation of Mouse Hepatic -Amino-β-Carboxymuconate--Semialdehyde Decarboxylase, a Key Enzyme in the Tryptophan-Nicotinamide Adenine Dinucleotide Pathway, by Hepatocyte Nuclear Factor 4 and Peroxisome Proliferator-Activated Receptor

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Nicotinamide adenine dinucleotide (NAD) plays a critical role in the maintenance of cellular energy homeostasis. -Amino-β-carboxymuconate--semialdehyde decarboxylase (ACMSD) is the key enzyme regulating de novo synthesis of NAD from L-tryptophan (Trp), designated the Trp-NAD pathway. Acmsd gene expression was found to be under the control of both hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor (PPAR). Constitutive expression of ACMSD mRNA levels were governed by HNF4 and downregulated by activation of PPAR by the ligand Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid]), as revealed by studies with hepatic HNF4-null mice and PPAR-null mice, respectively. Transient transfection and electrophoretic mobility shift analyses showed an HNF4 binding site in the Acmsd gene promoter that directed transactivation of reporter gene constructs by HNF4. The Acmsd promoter was not responsive to PPAR in transactivation assays. Wy-14,643 treatment decreased HNF4 protein levels in wild-type, but not PPAR-null, mouse livers, with no changes in HNF4 mRNA. These results show that Wy-14,643, through PPAR, post-transcriptionally down-regulates HNF4 protein levels, leading to reduced expression of the HNF4 target gene Acmsd.

Address correspondence to: Dr. Frank J. Gonzalez, Building 37, Room 3106, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. E-mail: fjgonz{at}helix.nih.gov

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