Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression.
Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression.
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丁酸钠通过上调肝脏 GLP-1R 表达来减少高脂饮食诱导的非酒精性脂肪性肝炎
DOI：
10.1038/s12276-018-0183-1
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发表时间：
2018-12-03
影响因子：
12.8
通讯作者：
Fan JG
中科院分区：
文献类型：
--
作者：
Zhou D;Chen YW;Zhao ZH;Yang RX;Xin FZ;Liu XL;Pan Q;Zhou H;Fan JG
胰高血糖素样肽-1 （GLP-1）具有广泛的生物活性，可通过直接激活G蛋白偶联受体B类家族和间接非受体介导途径调节代谢过程。在动物模型中，GLP-1受体（GLP-1R）激动剂对非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）有显著的治疗作用。然而，临床研究表明，GLP-1治疗对部分NAFLD患者的肝脂肪变性效果甚微，提示这些患者可能出现GLP-1耐药。众所周知，肠道代谢物丁酸钠（NaB）可促进肠道L细胞分泌GLP-1。然而，尚不清楚NaB是否能改善NAFLD患者的肝脏GLP-1反应性。在本研究中，我们发现NAFLD患者血清GLP-1水平与正常对照相似，但肝脏GLP-1R表达在NAFLD患者中明显下调。同样，在NAFLD小鼠模型中，喂食高脂肪饮食的小鼠肝脏GLP-1R表达降低，NaB治疗可逆转这一趋势，并伴有肝脏脂肪变性明显减轻。此外，NaB治疗还上调了肝脏p-AMPK/p-ACC和胰岛素受体/胰岛素受体底物-1的表达水平。此外，nab通过抑制独立于GPR43/GPR109a的组蛋白去乙酰酶-2，增强了HepG2细胞中GLP-1R的表达。这些结果表明，NaB能够通过促进肝脏GLP-1R的表达来阻止NAFL向NASH的发展。NaB是GLP-1增敏剂，是一种潜在的治疗辅助剂，可防止NAFL发展为NASH。
Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.
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影响因子：
7.7
作者：
Tolhurst G;Heffron H;Lam YS;Parker HE;Habib AM;Diakogiannaki E;Cameron J;Grosse J;Reimann F;Gribble FM
通讯作者：
Gribble FM
影响因子：
6.7
作者：
Svegliati-Baroni, Gianluca;Saccomanno, Stefania;Gastaldelli, Amalia
通讯作者：
Gastaldelli, Amalia
影响因子：
5.6
作者：
Park, Jin-Sun;Lee, Eun-Jung;Kim, Hee-Sun
通讯作者：
Kim, Hee-Sun
影响因子：
4.2
作者：
Ao, Na;Yang, Jing;Du, Jian
通讯作者：
Du, Jian
影响因子：
8.2
作者：
Smits MM;Tonneijck L;Muskiet MH;Kramer MH;Pouwels PJ;Pieters-van den Bos IC;Hoekstra T;Diamant M;van Raalte DH;Cahen DL
通讯作者：
Cahen DL