Facebook Pixel Code
Banner image
Adeli Lab


Molecular Biology of Lipoprotein Metabolism

A major focus of my laboratory’s research program has been in the area of lipoprotein metabolism particularly the synthesis and secretion of atherogenic lipoproteins by the liver. We have been investigating the regulation of plasma levels of cholesterol, triglycerides, and atherogenic lipoproteins (LDL, low density lipoproteins) by changes in the rate of secretion of lipoproteins by the liver.

The main protein moiety involved in lipoprotein production is apolipoprotein B (apoB) which is a 550 kDa protein made in both liver (full length apoB100) and the intestine (a truncated form, apoB48). ApoB is assembled with lipids including phospholipid, cholesterol, cholesterol ester, and triglyceride to form a lipoprotein particle which is then secreted into the blood circulation providing a source of these lipid substrates to peripheral tissues. Overproduction of these lipoproteins can lead to elevation in plasma cholesterol and triglyceride thus increasing the risk of atherosclerosis and coronary heart disease.

Up to later 1980’s, there was little understanding of the mechanisms regulating hepatic secretion of lipoproteins. Our laboratory was one of the first groups to initiate research in this area which has now been recognized as a very important mode of regulation of plasma lipid levels and thus risk of atherosclerosis. We initially investigated transcriptional and posttranscriptional regulation of apoB gene and found little evidence for the acute modulation of apoB at the transcription or mRNA levels.

Our attention was thus devoted to co-translational and posttranslational mechanisms that appeared to be the major determinants of the rate of apoB secretion. Studies over several years (1988-1997) resulted in elucidation of the key mechanisms of apoB regulation, including intracellular protein degradation and membrane translocation across the ER (endoplasmic reticulum). In a series of key papers over this period, we were able to delineate the mechanisms of apoB degradation in a human liver cell model, HepG2 cells.

A novel contribution of our group in studying apoB degradation has the use of a permeabilized cell model which has allowed us to focus on degradative systems in the cell operating in intracellular organelles including the ER.

Based on the use of this novel model system, we have now obtained evidence for the existence of multiple proteolytic systems operating the cell which affect apoB stability including the ubiquitin-proteasome system and other non-proteasomal cysteine proteases in the secretory pathway. This work is continuing in our laboratory and is currently supported by an operating grant the Heart and Stroke Foundation of Ontario.