title: Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation.
  
  
  OBJECTIVE
  We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH.
  
  
  METHODS
  CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH.
  
  
  RESULTS
  Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice.
  
  
  CONCLUSIONS
  In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.|Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Leandi
authors.initials: L
authors.lastname: Kruger
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Jewell
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Thiago de Almeida
authors.initials: Tde A
authors.lastname: Pereira
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Moylan
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 905 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC, 27710, USA. diehl004@mc.duke.edu.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053143:Caspase 2 / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications; D066273:Diet, Western; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010205:Pantothenic Acid / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology*
chemical_list: D000214:Acyl Coenzyme A; D014803:Vitamin B Complex; D010205:Pantothenic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; C090208:Casp2 protein, mouse; D053143:Caspase 2; D000111:Acetylcysteine
keywords: Caspase-2; Coenzyme A; N-Acetylcysteine; Nonalcoholic steatohepatitis; Pantothenate