Increased liver AGEs induce hepatic injury mediated through an OST48 pathway.
Increased liver AGEs induce hepatic injury mediated through an OST48 pathway.
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DOI：
10.1038/s41598-017-12548-4
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发表时间：
2017-09-25
影响因子：
4.6
通讯作者：
Forbes JM
中科院分区：
文献类型：
--
作者：
Zhuang A;Yap FY;Bruce C;Leung C;Plan MR;Sullivan MA;Herath C;McCarthy D;Sourris KC;Kantharidis P;Coughlan MT;Febbraio MA;Hodson MP;Watt MJ;Angus P;Schulz BL;Forbes JM
蛋白质寡糖转移酶48 （OST48）是内质网（ER）中蛋白质n -糖基化的组成部分，但也被认为是晚期糖基化终产物（AGE）的膜局部清除受体。肝内质网应激和AGE积累均与肝损伤有关。因此，本研究的目的是增加OST48的表达，并研究其对肝脏功能和结构的影响。每组8周龄雄性小鼠（n = 10-12 /组）过表达OST48基因，多利基-二磷酸寡糖-蛋白糖基转移酶（DDOST+/−），随访24周，随机分配到低或高AGE含量的饮食中。在研究的第24周，增加OST48表达或食用高ages饮食都会损害肝功能，并适度增加肝纤维化，但在没有脂肪变性的情况下，它们的联合显著加重了肝损伤。DDOST+/−小鼠的门静脉输送和肝脏AGEs积累增加，导致中枢性肥胖、胰岛素分泌缺陷、燃料使用转向脂肪和酮酸，以及肝糖原积累导致肝脏变大、肝脏内质网和氧化应激。这项研究揭示了OST48和AGE轴在内质网应激、燃料利用变化和葡萄糖耐受不良引起的肝损伤中的新作用。
The protein oligosaccharyltransferase-48 (OST48) is integral to protein N-glycosylation in the endoplasmic reticulum (ER) but is also postulated to act as a membrane localised clearance receptor for advanced glycation end-products (AGE). Hepatic ER stress and AGE accumulation are each implicated in liver injury. Hence the objective of this study was to increase the expression of OST48 and examine the effects on hepatic function and structure. Groups of 8 week old male mice (n = 10–12/group) over-expressing the gene for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/−), were followed for 24 weeks, while randomised to diets either low or high in AGE content. By week 24 of the study, either increasing OST48 expression or consumption of high AGE diet impaired liver function and modestly increased hepatic fibrosis, but their combination significantly exacerbated liver injury in the absence of steatosis. DDOST+/− mice had increased both portal delivery and accumulation of hepatic AGEs leading to central adiposity, insulin secretory defects, shifted fuel usage to fatty and ketoacids, as well as hepatic glycogen accumulation causing hepatomegaly along with hepatic ER and oxidative stress. This study revealed a novel role of the OST48 and AGE axis in hepatic injury through ER stress, changes in fuel utilisation and glucose intolerance.
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影响因子：
3.7
作者：
Patel R;Baker SS;Liu W;Desai S;Alkhouri R;Kozielski R;Mastrandrea L;Sarfraz A;Cai W;Vlassara H;Patel MS;Baker RD;Zhu L
通讯作者：
Zhu L
DOI：
10.1016/j.bbadis.2015.04.005
发表时间：
2015-07-01
影响因子：
6.2
作者：
Chan, Stanley M. H.;Zeng, Xiao-Yi;Ye, Ji-Ming
通讯作者：
Ye, Ji-Ming
DOI：
10.1152/ajpendo.90617.2008
发表时间：
2008-12-01
影响因子：
5.1
作者：
Andrikopoulos, Sofianos;Blair, Amy R.;Proietto, Joseph
通讯作者：
Proietto, Joseph
影响因子：
13.5
作者：
Arteel, Gavin E
通讯作者：
Arteel, Gavin E
影响因子：
5.5
作者：
Cai, Weijing;He, John Cijiang;Vlassara, Helen
通讯作者：
Vlassara, Helen