title: Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH.
abstract: BACKGROUND
  We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear.
  
  
  OBJECTIVE
  Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life.
  
  
  METHODS
  Female mice were fed either a control (C, 7%kcal fat) or HF (45%kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, sirtuin expression (Sirt1, Sirt3), and the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erbα, Rev-Erbβ, RORα, and Srebp1c) were measured in offspring livers.
  
  
  RESULTS
  Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD(+)/NADH (p<0.05, HF/HF vs C/C), Sirt1 (p<0.001, HF/HF vs C/C), Sirt3 (p<0.01, HF/HF vs C/C), perturbed clock gene expression, and elevated expression of genes involved lipid metabolism, such as Srebp1c (p<0.05, C/HF and HF/HF vs C/C).
  
  
  CONCLUSIONS
  Our results suggest that exposure to excess dietary fat during early and post-natal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced sirtuin abundance, and desynchronized clock gene expression.
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK; University of Colorado Anschutz Medical Campus, Endocrinology, Metabolism and Diabetes, Aurora, USA. Electronic address: Kimberley.bruce@ucdenver.edu.
authors.forename: Kimberley D
authors.initials: KD
authors.lastname: Bruce
authors.affiliation: Poznań University of Life Sciences, Department of Animal Physiology and Biochemistry, Poznań, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Szczepankiewicz
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Sihota
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Manoj
authors.initials: M
authors.lastname: Ravindraanandan
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Thomas
authors.affiliation: Centre for Biological Sciences, Institute of Developmental Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Lillycrop
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Burdge
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hanson
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Byrne
authors.affiliation: Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Felino R
authors.initials: FR
authors.lastname: Cagampang
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D017440:Photoperiod; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C498262:Nr1d1 protein, mouse; C499650:Nr1d2 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C539739:Rora protein, mouse; C525046:Sirt3 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D056926:CLOCK Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D056566:Sirtuin 3
keywords: Aging; Circadian; Development; Fatty liver; High fat; Maternal diet