Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis
Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis
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DOI：
10.1016/j.exger.2015.05.009
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发表时间：
2015-09-01
影响因子：
3.9
通讯作者：
Gallardo, Nilda
中科院分区：
文献类型：
--
作者：
Salamanca, Aurora;Barcena, Brenda;Gallardo, Nilda
衰老与脂质代谢的改变和非酒精性脂肪肝患病率的增加有关。然而，衰老过程中脂肪在肝脏中积累的机制仍然不完全清楚。在本研究中，我们研究了可能导致肝脏脂肪变性随年龄增长而发展的潜在变化。为此，我们分析了3个月和24个月大的Wistar大鼠肝脏中参与脂质代谢的关键转录因子，如ChREBP，Foxo 1，Foxa 2和SREBP-1c的表达和亚细胞定位。此外，我们研究了细胞内的ChREBP再分布响应禁食/再喂养过渡。老年大鼠的特点是肝脏脂肪变性，低血清酮体水平和餐后高胰岛素血症。Foxa 2的胞浆定位和表达减少证实了这些观察结果，而ChREBP的表达显著上调，主要定位于细胞核。因此，脂肪生成和β-氧化基因的表达分别上调或下调。此外，细胞内的再分布ChREBP响应禁食/再喂养的过渡也受损，在老年动物。此外，血清酮体水平和ChREBP的核定位之间的负相关性，观察到只有在成年大鼠，而不是在老年大鼠。综上所述，这些数据表明，与年龄相关的功能失调的ChREBP适应，在营养状态的变化，可能有助于肝脏脂肪变性的发展与衰老。(C)2015 Elsevier Inc. All rights reserved.
Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging. To this end, we analyzed the expression and the subcellular localization of key transcriptional factors involved in lipid metabolism such as ChREBP, Foxo1, Foxa2 and SREBP-1c in the liver of 3-and 24-month old Wistar rats. In addition, we studied the intracellular redistribution of ChREBP in response to fasting/refeeding transition. Old rats were characterized by hepatic steatosis, low serum ketone body levels and postprandial hyperinsulinemia. These observations were paralleled by the cytoplasmic localization and decreased expression of Foxa2, while ChREBP expression was markedly up-regulated and mainly localized in the nucleus. Consequently, the expression of lipogenic and beta-oxidation genes was up-regulated or down-regulated, respectively. Besides, the intracellular redistribution of ChREBP in response to fasting/refeeding transition was also impaired in old animals. Additionally, a negative correlation between serum ketone body levels and the nuclear localization of ChREBP was observed only in adult but not in old rats. Taken together, these data suggest that an age-related dysfunctional adaptation of ChREBP, in response to changes in the nutritional state, might contribute to the development of liver steatosis with aging. (C) 2015 Elsevier Inc. All rights reserved.