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Published on: March 14, 2015
Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed
Kimberley D Bruce1, Dawid Szczepankiewicz2, Kiran K Sihota3
1Institute 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.
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 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).
Conclusion:
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.
