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Title: Increased liver AGEs induce hepatic injury mediated through an OST48 pathway.
Austin Authors: Zhuang, Aowen;Yap, Felicia Yt;Bruce, Clinton;Leung, Christopher ;Plan, Manuel R;Sullivan, Mitchell A;Herath, Chandana;McCarthy, Domenica;Sourris, Karly C;Kantharidis, Phillip;Coughlan, Melinda T;Febbraio, Mark A;Hodson, Mark P;Watt, Matthew J;Angus, Peter W ;Schulz, Benjamin L;Forbes, Josephine M
Affiliation: Mater Clinical School, University of Queensland, St Lucia, Australia
School of Pharmacy, University of Queensland, Woolloongabba, Australia
Biomedicine Discovery Program and the Department of Physiology, Monash University, Clayton, Australia
School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Australia
Glycation and Diabetes, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia
School of Medicine, University of Queensland, St Lucia, Australia
Diabetic Complications Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
Department of Immunology and Medicine, Central and Eastern Clinical School, AMREP Precinct, Monash University, Clayton, Australia
Institute for Physical Activity and Nutrition (IPAN), Deakin University, Burwood, Australia
Metabolomics Australia, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Australia
Centre for Nutrition and Food Science, Queensland Alliance for Agriculture and Food Innovation, University of Queensland, St Lucia, Australia
Medicine (University of Melbourne)
Issue Date: 25-Sep-2017
Date: 2017-09-25
Publication information: Scientific Reports 2017; 7(1): 12292
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 (nā€‰=ā€‰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.
DOI: 10.1038/s41598-017-12548-4
ORCID: 0000-0002-7409-6629
Journal: Scientific Reports
PubMed URL: 28947796
Type: Journal Article
Appears in Collections:Journal articles

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