The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice.
The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice.
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DOI：
10.1371/journal.pone.0138307
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Klaassen CD
中科院分区：
文献类型：
--
作者：
Fu ZD;Cui JY;Klaassen CD
Sirtuin 1(Sirt1)是一种依赖NAD+的蛋白去乙酰基酶，被认为介导了热量限制(CR)的许多促进健康的作用。我们最近报道，短期CR增加了小鼠的胆汁酸(BA)池大小，可能是由于增加了肝脏中BA的合成。鉴于Sirt1在调节糖、脂和BA代谢中的重要作用，我们假设CR诱导的bas增加是Sirt1依赖的。为了解决这个问题，本研究使用了Sirt1功能丧失(肝脏敲除，LKO)或Sirt1功能获得(全身转基因，TG)的转基因小鼠。将Sirt1-LKO、野生型和Sirt1-TG三种基因型鼠随机分为随机组和40%CR组，每组饲养1个月。从肠肝循环的不同隔室中提取BA，然后用UPLC-MS/MS分析BA，CR增加了BA池的大小和血清、胆囊壁和小肠中的BA总量。CR诱导的BA池大小增加与BA合成限速酶Cyp7a1表达增加的趋势有关。然而，与假设相反，CR诱导的BA池大小和Cyp7a1表达的增加仍然存在于肝脏中，Sirt1的表达在肝脏中被消融，并在全身过表达Sirt1后完全被抑制。此外，在BA组成方面，CR增加了12个α-羟基化BA的比例，而不考虑Sirt1基因。总之，CR诱导的BA池大小、BA谱和BA相关基因表达的变化似乎不依赖于Sirt1。
Sirtuin 1 (Sirt1) is an NAD+-dependent protein deacetylase that is proposed to mediate many health-promoting effects of calorie restriction (CR). We recently reported that short-term CR increased the bile acid (BA) pool size in mice, likely due to increased BA synthesis in liver. Given the important role of Sirt1 in the regulation of glucose, lipid, as well as BA metabolism, we hypothesized that the CR-induced increase in BAs is Sirt1-dependent. To address this, the present study utilized genetically-modified mice that were Sirt1 loss of function (liver knockout, LKO) or Sirt1 gain of function (whole body-transgenic, TG). Three genotypes of mice (Sirt1-LKO, wild-type, and Sirt1-TG) were each randomly divided into ad libitum or 40% CR feeding for one month. BAs were extracted from various compartments of the enterohepatic circulation, followed by BA profiling by UPLC-MS/MS. CR increased the BA pool size and total BAs in serum, gallbladder, and small intestine. The CR-induced increase in BA pool size correlated with the tendency of increase in the expression of the rate-limiting BA-synthetic enzyme Cyp7a1. However, in contrast to the hypothesis, the CR-induced increase in BA pool size and Cyp7a1 expression was still observed with ablated expression of Sirt1 in liver, and completely suppressed with whole-body overexpression of Sirt1. Furthermore, in terms of BA composition, CR increased the ratio of 12α-hydroxylated BAs regardless of Sirt1 genotypes. In conclusion, the CR-induced alterations in BA pool size, BA profiles, and expression of BA-related genes do not appear to be dependent on Sirt1.