Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21.
Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21.
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DOI：
10.1053/j.gastro.2013.10.059
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发表时间：
2014-02
期刊：
影响因子：
29.4
通讯作者：
Zang M
中科院分区：
文献类型：
--
作者：
Li Y;Wong K;Giles A;Jiang J;Lee JW;Adams AC;Kharitonenkov A;Yang Q;Gao B;Guarente L;Zang M
肝细胞衍生的激素成纤维细胞生长因子21（FGF 21）是代谢的一种类胡萝卜素调节剂。NAD+依赖性脱乙酰酶SIRT 1通过多种营养传感器调节脂肪酸代谢。肝脏中SIRT 1的过度表达减少了肥胖小鼠的脂肪变性和葡萄糖耐受不良。我们研究了SIRT控制小鼠肝脂肪变性的机制。将具有肝脏特异性Sirt 1破坏的小鼠（SIRT 1 LKO小鼠）及其野生型同窝出生的小鼠（对照）分成正常食物饮食、禁食24小时或禁食24小时然后喂食6小时的组。收集肝组织并通过组织学、基因表达谱和实时PCR测定进行分析。将人HepG 2细胞与SIRT 1的药理学激活剂（白藜芦醇或SRT 1720）一起孵育，并通过线粒体氧化和免疫印迹分析进行评估。使用腺病毒载体在SIRT 1 LKO小鼠中过表达FGF 21。能量消耗通过间接量热法评估。禁食诱导对照小鼠肝脏中的脂质沉积，但SIRT 1 LKO小鼠中出现严重的肝脏脂肪变性。基因表达分析表明，禁食上调对照组肝脏中的FGF 21，但SIRT 1 LKO小鼠没有。与禁食对照小鼠相比，禁食SIRT 1 LKO小鼠肝脏和循环中FGF 21水平降低与脂肪酸氧化和酮生成相关基因的肝脏表达降低以及控制脂肪生成的基因表达增加相关。白藜芦醇或SRT 1720各自增加HepG 2细胞中FGF 21启动子（-2070/+117）的转录活性以及FGF 21 mRNA和蛋白质的水平。令人惊讶的是，SIRT 1 LKO小鼠出现了迟发性肥胖，全身能量消耗受损。在SIRT 1 LKO小鼠中，FGF 21的肝脏过表达增加了调节脂肪酸氧化的基因的表达，减少了禁食诱导的脂肪变性，减轻了肥胖，增加了能量消耗，并促进了白色脂肪组织的布朗宁。SIRT 1介导的FGF 21活化可预防禁食引起的肝脏脂肪变性。这种肝细胞来源的内分泌信号似乎调节基因的表达，这些基因控制白色脂肪组织中的棕色脂肪样程序、能量消耗和肥胖。激活SIRT 1或FGF 21的策略可用于治疗脂肪肝和肥胖症。
The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The NAD+-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT controls hepatic steatosis in mice. Mice with liver-specific disruption of Sirt1 (SIRT1 LKO mice) and their wild-type littermates (controls) were divided into groups that were placed on normal chow diets, fasted for 24 hrs, or fasted for 24 hrs and then fed for 6 hrs. Liver tissues were collected and analyzed by histologic, gene expression profile, and real-time PCR assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and assessed by mitochondrial oxidation and immunoblot analyses. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry. Fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting upregulated FGF21 in livers of control, but not SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased transcriptional activity of the FGF21 promoter (–2070/+117) and levels of FGF21 mRNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue. SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 might be used to treat fatty liver disease and obesity.
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影响因子：
3.5
作者：
Izumiya, Yasuhiro;Bina, Holly A.;Ouchi, Noriyuki;Akasaki, Yuichi;Kharitonenkov, Alexei;Walsh, Kenneth
通讯作者：
Walsh, Kenneth
影响因子：
4.8
作者：
Ponugoti, Bhaskar;Kim, Dong-Hyun;Kemper, Jongsook Kim
通讯作者：
Kemper, Jongsook Kim
影响因子：
10.5
作者：
Chen, Danica;Bruno, Joanne;Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
5.6
作者：
Kharitonenkov, Alexei;Dunbar, James D.;Shanafelt, Armen B.
通讯作者：
Shanafelt, Armen B.
影响因子：
29
作者：
Banks AS;Kon N;Knight C;Matsumoto M;Gutiérrez-Juárez R;Rossetti L;Gu W;Accili D
通讯作者：
Accili D