Regulation of mouse hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, a key enzyme in the tryptophan-nicotinamide adenine dinucleotide pathway, by hepatocyte nuclear factor 4alpha and peroxisome proliferator-activated receptor alpha.
Nicotinamide adenine dinucleotide (NAD) plays a critical role in the maintenance of cellular energy homeostasis. alpha-Amino-beta-carboxymuconate-epsilon-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 4alpha (HNF4alpha) and peroxisome proliferator-activated receptor alpha (PPARalpha). Constitutive expression of ACMSD mRNA levels were governed by HNF4alpha and downregulated by activation of PPARalpha by the ligand Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid]), as revealed by studies with hepatic HNF4alpha-null mice and PPARalpha-null mice, respectively. Transient transfection and electrophoretic mobility shift analyses showed an HNF4alpha binding site in the Acmsd gene promoter that directed transactivation of reporter gene constructs by HNF4alpha. The Acmsd promoter was not responsive to PPARalpha in transactivation assays. Wy-14,643 treatment decreased HNF4alpha protein levels in wild-type, but not PPARalpha-null, mouse livers, with no changes in HNF4alpha mRNA. These results show that Wy-14,643, through PPARalpha, post-transcriptionally down-regulates HNF4alpha protein levels, leading to reduced expression of the HNF4alpha target gene Acmsd.
Shin
Mariko
M
Laboratory of Metabolism, Building 37, Room 3106, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kim
Insook
I
Inoue
Yusuke
Y
Kimura
Shioko
S
Gonzalez
Frank J
FJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002262:Carboxy-Lyases / Q000235:genetics*; D002522:Chlorocebus aethiops; D015971:Gene Expression Regulation, Enzymologic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D024363:Transcription Initiation Site; D014162:Transfection; D014364:Tryptophan / Q000378:metabolism
D051557:Hepatocyte Nuclear Factor 4; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D009243:NAD; C006253:pirinixic acid; D014364:Tryptophan; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase