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Sci Rep. 2017 Sep 25;7(1):12292. doi: 10.1038/s41598-017-12548-4.

Increased liver AGEs induce hepatic injury mediated through an OST48 pathway.

Author information

1
Glycation and Diabetes, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
2
School of Medicine, University of Queensland, St Lucia, Australia.
3
Diabetic Complications Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
4
Department of Immunology and Medicine, Central and Eastern Clinical School, AMREP Precinct, Monash University, Clayton, Australia.
5
Institute for Physical Activity and Nutrition (IPAN), Deakin University, Burwood, Australia.
6
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia.
7
Metabolomics Australia, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Australia.
8
Centre for Nutrition and Food Science, Queensland Alliance for Agriculture and Food Innovation, University of Queensland, St Lucia, Australia.
9
School of Pharmacy, University of Queensland, Woolloongabba, Australia.
10
Biomedicine Discovery Program and the Department of Physiology, Monash University, Clayton, Australia.
11
School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Australia.
12
Glycation and Diabetes, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia. Josephine.Forbes@mater.uq.edu.au.
13
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia. Josephine.Forbes@mater.uq.edu.au.
14
Mater Clinical School, University of Queensland, St Lucia, Australia. Josephine.Forbes@mater.uq.edu.au.

Abstract

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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