Project 173614

In individuals with diabetes, up to 80% of deaths are attributed to heart disease resulting from elevated cholesterol and triglyceride (TG) in the blood. Apolipoprotein B (apoB) is a protein that is made in the liver and released into the blood bound to cholesterol and TG. High level of apoB, which are directly related to high level of cholesterol, is an early indicator of heart disease. ApoB expression and secretion is believed to be controlled by multiple factors including insulin, but we still know very little about the precise regulatory mechanisms. Our laboratory has recently discovered a previously unknown protein called p110 that interacts with the 5' untranslational region of the apoB mRNA and is regulated by insulin. The overall objective of this project is to clarify how abnormal plasma and hepatic levels of apoB-associated cholesterol and TG are able to reduce the responsiveness of hepatocytes to insulin. Cellular factors/proteins that are associated with apoB expression will also be examined. The efficiency of apoB production is closely linked to the folding and maturation of nascent apoB peptide in the endoplasmic reticulum (ER). We hypothesize that apoB overproduced and largely incorrectly folded may induce accumulation of apoB in hepatocytes ER. This accumulation induces hepatic insulin resistance by causing ER stress. We will further identify the intracellular location where the interactions between apoB and other cellular proteins/factors such as p110 occur. It is possible that mis- localization of these interactions could cause hepatocytes no longer respond to insulin, resulting in a disease state. The studies outlined in this application will enhance our understanding of the mechanisms controlling the lipid-associated apoB protein. Knowledge derived from these studies may also allow us to better tailor our therapeutic approaches to combat diabetes and cardiovascular disease.