Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

Abstract

The protein oligosaccharyltransferase-48 (OST48/AGE-R1) 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). AGE accumulation is implicated in liver injury, diabetic kidney disease and diabetes-associated metabolic disorders. To date, however, there has been minimal investigation into the role of OST48 in kidney and liver function under either physiological or diabetic conditions. Here we have used both global (DDOST+/-) and targeted (podocyte specific; DDOST+/-Pod-Cre ) knock-in mouse models to induce subtle increases in OST48.The burden of OST48 ligands, AGEs in these models, was modified by either dietary intervention or by the induction of diabetes to delineate the effects of increasing OST48 on the kidney and liver metabolome and proteome. Given previous studies, our postulate was that increasing OST48 would improve liver and kidney function in diabetes by facilitating removal of AGEs from the body.In the first study, we examined hepatic function and structure following global knock in of OST48 in combination with a therapeutic reduction in dietary AGE intake. Global knock-in of OST48 increased protein OST48 in the gastrointestinal tract, where it was highest in the duodenum. Both increasing gastrointestinal OST48 expression and/or greater consumption of AGEs modestly impaired liver function resulting in hepatic fibrosis. However, a combination of both high AGE dietary consumption and increased OST48 expression significantly exacerbated liver injury, but this was in the absence of steatosis. Interestingly, DDOST+/-mice had increased portal vein delivery and accumulation of hepatic AGEs which were associated with central adiposity, insulin secretory defects, shifting of fuel usage to fatty and keto-acids, and hepatic glycogen accumulation. These culminated in hepatomegaly along with hepatic ER and oxidative stress. This work is significant in that it revealed a novel role of the OST48 and AGE axis as a two-hit model of hepatic injury through ER stress, changes in fuel utilisation and impaired glucose tolerance.Our second and third studies aimed to delineate the physiological role of OST48 in the kidney through a global and podocyte-specific knock-in of OST48. Firstly, we investigated whether increased AGE excretion facilitated by modest increases in OST48, could prevent the development of diabetic kidney disease. This body of work is particularly significant, as to date there have been no studies examining whether elevating OST48 in diabetes is reno-protective, despite associative studies suggesting that a loss of OST48 is a pathological contributor to diabetes complications.