Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH.
Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH.
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DOI：
10.1016/j.bbalip.2016.03.026
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Cagampang FR
中科院分区：
文献类型：
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作者：
Bruce KD;Szczepankiewicz D;Sihota KK;Ravindraanandan M;Thomas H;Lillycrop KA;Burdge GC;Hanson MA;Byrne CD;Cagampang FR
我们以前已经证明，妊娠期高脂肪（HF）喂养会引发成年后代非酒精性脂肪性肝炎（NASH）的发展。然而，其潜在机制尚不清楚。由于内源性分子钟可以调节肝脏脂质代谢，我们研究了在发育过程中暴露于HF饮食是否会改变肝脏时钟基因表达并导致晚年NASH发作。雌性小鼠喂食对照（C，7% kcal脂肪）或HF（45% kcal脂肪）饮食。后代喂食C或HF饮食，产生四个后代组：C/C、C/HF、HF/C和HF/HF。在后代肝脏中测量NAFLD进展、细胞氧化还原状态、沉默调节蛋白表达（Sirt 1、Sirt 3）、核心时钟基因（Clock、Bmal 1、Per 2、Cry 2）和参与脂质代谢的时钟控制基因（Rev-Erbα、Rev-Erbβ、RORα和Srebp 1c）的表达。喂食HF饮食的后代发展为NAFLD。然而，喂食HF饮食的母亲喂食HF的后代发展NASH，伴随显著降低的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），时钟基因表达紊乱，脂质代谢相关基因表达升高，如Srebp 1c（p < 0.05，C/HF和HF/HF相对于C/C）。我们的研究结果表明，暴露于过量的膳食脂肪在早期和出生后的生活增加的易感性，以发展NASH在成年期，涉及改变细胞氧化还原状态，减少sirtuin丰度，和desertified时钟基因表达。高脂肪饮食母亲的后代在以后的生活中表现出严重的脂肪肝。HF喂养与改变细胞氧化还原状态和减少sirtuin基因表达有关。HF喂养降低了核心时钟基因和脂肪生成转录因子的表达。在发育过程中暴露于HF饮食会导致严重脂肪肝疾病之前的肝脏代谢变化。
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. 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. 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. 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). 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. 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.