Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes.
Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes.
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DOI：
10.1002/hep.31871
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Alpini G
中科院分区：
文献类型：
--
作者：
Chen L;Wu N;Kennedy L;Francis H;Ceci L;Zhou T;Samala N;Kyritsi K;Wu C;Sybenga A;Ekser B;Dar W;Atkins C;Meadows V;Glaser S;Alpini G
人类非酒精性脂肪性肝病（NAFLD）的早期特征是肝脂肪变性，当肝脏显示微泡性脂肪变性、小叶炎症和细胞周围纤维化时，可能进展为非酒精性脂肪性肝炎（NASH）。促胰液素（SCT）/促胰液素受体（SCTR）轴通过下调miR-125 b信号传导促进胆汁淤积模型中的胆汁衰老和肝纤维化。我们的目的是评估破坏胆管SCT/SCTR/miR-125 b信号传导对NAFLD/NASH中肝脂肪变性、胆管衰老和肝纤维化的影响。在体内，4周雄性WT、Sct-/-和Sctr-/-小鼠喂食对照饮食（CD）或高脂饮食（HFD）16周。通过免疫组织化学（IHC）和qPCR测量人NAFLD/NASH肝脏样品和HFD小鼠肝脏中SCT/SCTR/miR-125 b轴的表达。在小鼠肝脏和人NAFLD/NASH肝脏样本中评估了胆汁/肝细胞衰老、导管反应和肝脏血管生成。通过定制的RT 2 Profiler PCR阵列和荧光素酶测定筛选并验证肝细胞中的miR-125 b靶脂肪生成基因。在人NAFLD/NASH样品和HFD小鼠的肝脏中，胆汁SCT/SCTR表达增加，而miR-125 b的表达降低。在人NAFLD/NASH样本以及HFD小鼠中观察到胆汁/肝细胞衰老、导管反应和肝脏血管生成，这些在Sct-/-和Sctr-/- HFD小鼠中有所减少。Elovl 1是miR-125 b靶向的脂肪生成基因，并且其在HFD小鼠肝细胞中的表达在Sct或Sctr敲除后也降低。粪便样品中的胆汁酸谱在WT小鼠和Sct-/-/Sctr-/-小鼠之间具有最大的变化。胆管SCT/SCTR/miR-125 b轴通过上调脂质生物合成基因Elovl 1促进肝脏脂肪变性。靶向胆管SCT/SCTR/miR-125 b轴可能是改善人NAFLD/NASH表型的关键。
Human non-alcoholic fatty liver disease (NAFLD) is characterized at early stages by hepatic steatosis, which may progress to nonalcoholic steatohepatitis (NASH) when the liver displays microvesicular steatosis, lobular inflammation, and pericellular fibrosis. The secretin (SCT)/secretin receptor (SCTR) axis promotes biliary senescence and liver fibrosis in cholestatic models through downregulation of miR-125b signaling. We aim to evaluate the effect of disrupting biliary SCT/SCTR/miR-125b signaling on hepatic steatosis, biliary senescence and liver fibrosis in NAFLD/NASH. In vivo, 4 wk male WT, Sct-/- and Sctr-/- mice were fed a control diet (CD) or high-fat diet (HFD) for 16 wks. The expression of SCT/SCTR/miR-125b axis was measured in human NAFLD/NASH liver samples and HFD mouse livers by immunohistochemistry (IHC) and qPCR. Biliary/hepatocyte senescence, ductular reaction and liver angiogenesis were evaluated in mouse liver and human NAFLD/NASH liver samples. miR-125b target lipogenesis genes in hepatocytes were screened and validated by custom RT2 Profiler PCR array and luciferase assay. Biliary SCT/SCTR expression was increased in human NAFLD/NASH samples and in livers of HFD mice, whereas the expression of miR-125b was decreased. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were observed in human NAFLD/NASH samples as well as HFD mice, which were decreased in Sct-/- and Sctr-/- HFD mice. Elovl1 is a lipogenesis gene targeted by miR-125b, and its expression was also decreased in HFD mouse hepatocytes following Sct or Sctr knockout. Bile acid profile in fecal samples have the greatest changes between WT mice and Sct-/-/Sctr-/- mice. The biliary SCT/SCTR/miR-125b axis promotes liver steatosis by upregulating lipid biosynthesis gene Elovl1. Targeting the biliary SCT/SCTR/miR-125b axis may be key for ameliorating phenotypes of human NAFLD/NASH.
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影响因子：
13.5
作者：
Glaser, Shannon;Lam, Ian P.;Franchitto, Antonio;Gaudio, Eugenio;Onori, Paolo;Chow, Billy K.;Wise, Candace;Kopriva, Shelley;Venter, Julie;White, Mellanie;Ueno, Yoshiyuki;Dostal, David;Carpino, Guido;Mancinelli, Romina;Butler, Wendy;Chiasson, Valorie;DeMorrow, Sharon;Francis, Heather;Alpini, Gianfranco
通讯作者：
Alpini, Gianfranco
影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
影响因子：
5
作者：
Kennedy, Lindsey L.;Hargrove, Laura A.;Francis, Heather L.
通讯作者：
Francis, Heather L.
影响因子：
6.5
作者：
Kakiyama, Genta;Marques, Dalila;Pandak, William M.
通讯作者：
Pandak, William M.
DOI：
10.1073/pnas.0903695106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Chu, Jessica Y. S.;Lee, Leo T. O.;Chow, Billy K. C.
通讯作者：
Chow, Billy K. C.