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.
Highlights
Chronic liver disease is increasing globally as a result of obesity and diabetes, with non-alcoholic fatty liver disease (NAFLD), the most common liver disorder[1]
The liver, is a site for the clearance of AGEs, and a target organ and expresses various AGE receptors including the receptor for advanced glycation end-products (RAGE)[9], advanced glycation end product-receptor 1 (OST48 known as AGE-R1)[10] and galectin-3 (AGE-R3)[11]
In fractionated liver tissue taken from DDOST+/− mice at the same time point, there was a significant increase in plasma membrane localisation of DDOST+/− fed on a high AGE diet (Fig. S1E)
Summary
Chronic liver disease is increasing globally as a result of obesity and diabetes, with non-alcoholic fatty liver disease (NAFLD), the most common liver disorder[1]. In chronic liver injury, hepatic expression of RAGE is significantly increased[14] and several studies in acute liver injury have identified that blockade of RAGE can ameliorate toxic, ischemic and cholestatic liver damage[15] Another AGE receptor, OST48, is thought to be responsible for the detoxification and clearance of AGEs and negative regulation of AGE pro-inflammatory signalling[16,17], and cellular oxidative stress[18]. A novel OST48-AGE pathway that leads to the onset of liver injury in combination with central adiposity and glucose intolerance, despite ample physical activity These results establish a previously unappreciated physiological trafficking role of OST48 in the gastrointestinal tract and liver, which when dysregulated result in liver injury
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