Increased liver AGEs induce hepatic injury mediated through an OST48 pathway

Aowen Zhuang, Felicia Yt Yap, Clinton Bruce, Chris Leung, Manuel R. Plan, Mitchell A Sullivan, Chandana B Herath, Domenica McCarthy, Karly C. Sourris, Phillip Kantharidis, Melinda T. Coughlan, Mark A. Febbraio, Mark P. Hodson, Matthew J. Watt, Peter Angus, Benjamin Luke Schulz, Josephine M. Forbes

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Article number12292
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

Zhuang, A., Yap, F. Y., Bruce, C., Leung, C., Plan, M. R., Sullivan, M. A., Herath, C. B., McCarthy, D., Sourris, K. C., Kantharidis, P., Coughlan, M. T., Febbraio, M. A., Hodson, M. P., Watt, M. J., Angus, P., Schulz, B. L., & Forbes, J. M. (2017). Increased liver AGEs induce hepatic injury mediated through an OST48 pathway. Scientific Reports, 7(1), [12292]. https://doi.org/10.1038/s41598-017-12548-4