title: Regulation of rat hepatic α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase, a key enzyme in the tryptophan- NAD pathway, by dietary cholesterol and sterol regulatory element-binding protein-2.
abstract: OBJECTIVE
  Nicotinic acid is one of the older drugs used to treat hyperlipidemia, the greatest risk factor of coronary heart disease. Nicotinic acid is also a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD). In mammals, α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) plays a key role in NAD biosynthesis from tryptophan. However, the relationship between ACMSD and cholesterol metabolism has not been clarified enough yet. The present study was performed to make clear the relationship between ACMSD and cholesterol metabolism using hypercholesterolemic rats and rat primary hepatocytes.
  
  
  METHODS
  Male Sprague-Dawley rats were fed a diet containing cholesterol for 10 days to induce hypercholesterolemia. The NAD levels in the plasma and liver and hepatic ACMSD activity were determined. In vitro study, the expression of ACMSD and the transcriptional factors that regulate cholesterol metabolism were determined using rat primary hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, a statin medication, by quantitative real-time PCR analysis and Western blotting analysis.
  
  
  RESULTS
  The hepatic NAD level of the hypercholesterolemic group was significantly higher than the control, and the hepatic ACMSD activity of this group was significantly suppressed. There was a significant negative correlation between the hepatic ACMSD activity and liver cholesterol levels. Additionally, in primary rat hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, ACMSD gene and protein expression was subjected to sterol-dependent regulation. This gene expression changed in parallel to sterol regulatory element-binding protein (SREBP)-2 expression.
  
  
  CONCLUSIONS
  These results provide the first evidence that ACMSD is associated with cholesterol metabolism, and ACMSD gene expression may be upregulated by SREBP-2.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsuda
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sato
authors.forename: Mako
authors.initials: M
authors.lastname: Yakushiji
authors.forename: Manami
authors.initials: M
authors.lastname: Koshiguchi
authors.forename: Shizuka
authors.initials: S
authors.lastname: Hirai
authors.forename: Yukari
authors.initials: Y
authors.lastname: Egashira
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics* / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000201:enzymology*; D008297:Male; D023421:Models, Animal; D009243:NAD / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D009243:NAD; C007997:25-hydroxycholesterol; D014364:Tryptophan; D019821:Simvastatin; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase