Increased Liver AGEs Induce Hepatic Injury Mediated Through an OST48 Pathway

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • Feeding Behavior
  • Glycation End Products, Advanced / adverse effects*
  • Glycation End Products, Advanced / blood
  • Glycation End Products, Advanced / metabolism
  • Hexosyltransferases / genetics
  • Hexosyltransferases / metabolism*
  • Humans
  • Liver / drug effects
  • Liver / pathology
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / pathology*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oxidative Stress / drug effects
  • Receptor for Advanced Glycation End Products / metabolism
  • Signal Transduction

Substances

  • Glycation End Products, Advanced
  • Membrane Proteins
  • Receptor for Advanced Glycation End Products
  • Ddost protein, mouse
  • Hexosyltransferases
  • OST48 protein, human