Bruce, K.D., Szczepankiewicz, D, Sihota, K.K., Ravindraanandan, M., Thomas, H., Lillycrop, K.A., Burdge, G.C., Hanson, M.A., Byrne, C.D. and Cagampang, F.R. (2016) Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1861 (7), 584-593. (doi:10.1016/j.bbalip.2016.03.026). (PMID:27040510)
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.
Aims: 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
39 the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erb?, Rev-Erb?, ROR?, 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
45 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).
Conclusion: Our results suggest that exposure to excess dietary fat during early and postnatal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced Sirtuin abundance, and desynchronised clock gene expression.
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