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

Abstract

BackgroundWe 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.AimsSince 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.MethodsFemale 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.ResultsOffspring 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).ConclusionOur 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.

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

“…In a mouse model of NASH it was found that HFD induces the susceptibility to develop NASH through desynchronized Clock gene expression and altered cellular redox status, accompanied by reduced sirtuin abundance [197]. HFD in mice is sufficient to induce the loss of circadian fluctuations of insulin secretion [199].…”

Sirtuins and nonalcoholic fatty liver disease

“…Interestingly, in a recent study, Bruce et al[46] indicated that exposure to excess dietary fat during early and post-natal life increases the susceptibility to develop NASH in adulthood and this was associated with reduced sirtuin abundance. Offspring fed a high fat diet (HFD) developed NAFLD while HFD-fed offspring of mothers fed a HFD diet developed NASH in combination of reduced NAD + /NADH, SIRT1, SIRT3 and increased expression of genes involved in lipid metabolism[46]. SIRT1 and SIRT3 are the most studied sirtuins; we will focus mainly on these two sirtuins, their mode of action and their role in NAFLD.…”

“…SIRT3 is the most investigated mitochondrial sirtuin, while SIRT1 has been shown to be expressed in various metabolic tissues including liver, adipose tissue, skeletal muscle, pancreas and brain. SIRT1 plays a key role in the development of NAFLD through its involvement in the regulation of both lipid and carbohydrate metabolism[45,46,63-66]. Studies in mice and in cultured cells have characterized SIRT1 as a metabolic sensor that has the potential to improve NAFLD.…”

Interaction between stress responses and circadian metabolism in metabolic disease

“…It has been shown that a high fat diet increases the incidence of NASH in adulthood, associated with altered cellular redox status, reduced sirtuin abundance, and desynchronized clock gene expression. 69 …”