Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH

Apr 5, 2016Biochimica et biophysica acta

Changes in cell oxidation, sirtuin levels, and body clock genes in mice with early-stage fatty liver disease

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Abstract

Offspring fed a high-fat diet developed non-alcoholic steatohepatitis (NASH) when their mothers were also on a high-fat diet.

NASH development was linked to significantly reduced NAD(+)/NADH levels in offspring of high-fat fed mothers.
Reduced expression of Sirt1 and Sirt3 was observed in offspring from mothers on a high-fat diet.
Altered expression of core clock genes associated with lipid metabolism was noted in the livers of affected offspring.
Elevated expression of lipid metabolism-related genes, such as Srebp1c, was found in high-fat diet offspring.

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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.

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Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH

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