Hepatic gene expression changes in aging and R-a-lipoic acid supplementation: Necroinflammatory phenotype, lipid synthesis regulation and circadian rhythms.

To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 months) and old (24 months) male Fischer 344 rats a diet with or without 0.2% (w/w) R-a-lipoic acid (LA) for two weeks. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profile. Results showed an increase in pro-inflammatory gene expression in the aging liver, with increased immune cell function and tissue remodeling genes, representing 45% of the age-related transcriptome changes. Increased inflammation was corroborated by increases in soluble ICAM1 levels with age. There were also observed age-related increases in transcription of genes related to lipid and cholesterol synthesis including Acetyl CoA Carboxylase (Acacb) and Fatty acid Synthase (Fasn). Supplementation of old animals with LA did not reverse this necro-inflammatory phenotype, yet limited age-associated hepatic dyslipidemia. Dietary LA further affected a small but concerted number of hepatic genes regardless of age. These included declines in lipid and bile synthesis genes. Decline in lipid synthesis genes was further corroborated by a decrease in Fasn and Acc protein levels. Intriguingly, LA also altered the expression of genes governing circadian rhythm, most notably Bmal1, Npas2, and Per2, which changed in a coordinated manner with respect to their rhythmic transcription. Thus, advanced age is associated with a necro-inflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with energy metabolism and circadian rhythm regardless of age.为探究年龄与硫辛酸（lipoic acid, LA）补充干预对肝脏基因表达的影响，本研究对3月龄年轻雄性费希尔344（Fischer 344）大鼠与24月龄老年雄性同品系大鼠饲喂添加或不添加0.2%（重量比，w/w）R-α-硫辛酸的日粮，干预周期为两周。从肝脏组织中分离得到的总RNA通过Affymetrix微阵列（Affymetrix microarray）进行检测，以分析转录表达谱的变化。结果显示，衰老大鼠肝脏内的促炎基因表达上调，免疫细胞功能与组织重塑相关基因的表达亦同步升高，此类变化占年龄相关转录组改变的45%。随着年龄增长，可溶性细胞间黏附分子1（soluble ICAM1）水平升高，这进一步验证了炎症反应的增强。研究同时观察到，与年龄相关的脂质及胆固醇合成相关基因的转录水平上调，包括乙酰辅酶A羧化酶（Acetyl CoA Carboxylase, Acacb）与脂肪酸合酶（Fatty acid Synthase, Fasn）。对老年大鼠补充硫辛酸未能逆转该坏死炎症表型，但可部分缓解年龄相关的肝脏血脂异常。无论受试动物年龄如何，膳食补充硫辛酸均可影响少量但协同调控的肝脏基因群，其中包括脂质与胆汁合成相关基因的表达下调。脂质合成基因的表达下调进一步通过脂肪酸合酶（Fasn）与ACC蛋白水平的降低得到验证。值得注意的是，硫辛酸还可改变调控生物钟节律（circadian rhythm）的基因表达，其中尤以Bmal1、Npas2及Per2为著，这些基因的节律性转录呈现协同变化模式。综上，高龄与坏死炎症表型及脂质合成增强密切相关，而长期补充硫辛酸可在不考虑年龄的情况下，调控与能量代谢及生物钟节律相关的肝脏基因表达。