title: Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ≈ C57BL/6J ≈ C3H/HeJ < 129S1/SvImJ ≈ CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor α (PPARα)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARα-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas 72079, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.forename: Tetyana
authors.initials: T
authors.lastname: Kobets
authors.forename: Kristy
authors.initials: K
authors.lastname: Kutanzi
authors.forename: Igor
authors.initials: I
authors.lastname: Koturbash
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shymonyak
authors.forename: Leonard
authors.initials: L
authors.lastname: Collins
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Ross
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000821:Animal Feed; D000818:Animals; D002794:Choline / Q000008:administration & dosage*; D002796:Choline Deficiency / Q000150:complications*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004032:Diet; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005492:Folic Acid / Q000008:administration & dosage*; D005494:Folic Acid Deficiency / Q000150:complications*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress; D040081:Protein Array Analysis; D059467:Transcriptome
chemical_list: D003577:Cytochrome P-450 Enzyme System; D005492:Folic Acid; D002794:Choline