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

https://doi.org/10.1016/j.bbalip.2016.03.026Get rights and content
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Highlights

  • Offspring of mothers fed a high fat diet show severe fatty liver in later life.

  • HF feeding is associated with altered cellular redox status and reduced sirtuin gene expression.

  • HF feeding desynchronises the expression of core clock genes and lipogenic transcription factors.

  • Exposure to a HF diet during development causes changes in liver metabolism that precede severe fatty liver disease.

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 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.

Abbreviations

NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
HF
high fat
C
control
sirt1
sirtuin 1
sirt3
sirtuin 3
Clock
circadian locomotor output cycles kaput
Per2
Bmal1 (also called Arntl1), period 2
Cry2
cryptochrome 2
RORα
retinoic acid receptor-related orphan receptor alpha
Srebp1c
sterol regulatory element binding protein-1c
NAD
nicotinamide adenine dinucleotide
OPN
osteopontin

Keywords

High fat
Maternal diet
Fatty liver
Development
Aging
Circadian

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This work was supported by the BBSRC Grant Number BB/G01812X/1.