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

Abstract

Nicotinamide adenine dinucleotide (NAD) plays a critical role in the maintenance of cellular energy homeostasis. ␣-Amino-␤-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␣, posttranscriptionally down-regulates HNF4␣ protein levels, leading to reduced expression of the HNF4␣ target gene Acmsd.

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

“…Differentially expressed genes associated with a functional network related to AA and lipid metabolism were identified, which revealed that PPARa regulates proteins involved in AA metabolism, and this may occur indirectly, mediated through HNF4a. Previous studies have reported the established ability of PPARa to down-regulate the expression of HNF4a (Hertz et al 1995(Hertz et al , 1996Marrapodi and Chiang 2000;Shin et al 2006) and demonstrated an association between HNF4a and the expression of some AACE (Nitsch et al 1993;Odom et al 2004;Shin et al 2006).…”

Effect of Dietary Phytol on the Expression of α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase, a Key Enzyme of Tryptophan-niacin Metabolism, in Rats

“…It has only recently been reported that PPs including fibrates down-regulated the expression of hepatic ACMSD mRNA in mice, and it was also demonstrated by using hepatic PPAR-null mice and HNF4-null mice that the constitutive expression of ACMSD mRNA was positively controlled by HNF4 and down-regulated by the activation of PPAR. 14) We have also reported that the downregulation of rat hepatic ACMSD mRNA caused by polyunsaturated fatty acids was not mediated by a PPAR-dependent pathway, although down-regulation by peroxisome proliferators was PPAR-dependent. 15) Our initial studies showed that rats fed with a phytol diet had an increased level of NAD in the blood, and decreased hepatic ACMSD activity, this occurring in a dose-dependent manner.…”

“…[11][12][13] Moreover, fibrate affects the hepatic ACMSD gene expression via PPAR activation. 14,15) However, only a few studies have reported the effect of dietary phytochemicals on ACMSD expression in vivo and in vitro.…”

NicotinamideN-Oxidation by CYP2E1 in Human Liver Microsomes

“…NAM clearance metabolites have recently been proposed as potential biomarkers of peroxisome proliferator-activated receptor-a activation by fibrates (Delaney et al, 2005;Zhen et al, 2007). The large increase in NAM metabolites has been attributed to the suppression of the enzyme a-amino-b-carboxymuconate-«-semialdehyde decarboxylase by peroxisome proliferator-activated receptor-a, which increases the tryptophan flux through the quinolinic-nicotinamide adenine dinucleotide pathway, giving rise eventually to NAM clearance products (Sanada, 1985;Fukuoka et al, 2002;Shin et al, 2006). Our results suggest that NAM N-oxide might actually be a more direct biomarker of CYP2E1 provided that it shows the required specificity and correlation with CYP2E1 activity.…”