Principal Investigator Monty Krieger
The SR-Bs, including SR-BI and CD36, are members of the CD36 superfamily of proteins and are expressed on a variety of cell types and tightly bind anionic phospholipids. We cloned SR-BI as an SR and subsequently discovered that it can bind LDL and HDL. Indeed, it was the first physiologically relevant HDL receptor to be described. SR-BI is expressed primarily in liver and steroidogenic tissues. SR-BI, which in some cells is clustered in lipid rafts (e.g., caveolae) rather than coated pits, mediates selective cholesterol uptake from HDL by a mechanism distinct from the classic LDL receptor endocytic pathway.
After HDL binds to SR-BI, cholesterol is transferred to the cells and the cholesterol-depleted particle is released into the extracellular space - there is no lysosomal degradation. This mechanism is called 'selective lipid uptake'. We are using biochemical, biophysical, physiologic, molecular genetic and chemical biological approaches to study the structure and mechanism of action of SR-BI. For example, we have performed large scale, high throughput small molecule screens that have identified potent inhibitors of SR-BI. We have and continue to use these chemical probes combined with structure/activity relationship (SAR) analysis and mutagenesis and biophysical studies to investigate the molecular mechanisms underlying selective lipid uptake.
We have shown that SR-BI expression in vivo is coordinately regulated with cholesterol metabolism (e.g., steroidogeneis) and that genetic manipulation of its expression can significantly influence plasma HDL and biliary cholesterol concentrations. We have also been studying - in a close collaboration with Olivier Kocher at the Harvard Medical School - the mechanism by which the multiple PDZ-domain containing scaffold protein PDKZ1 regulates the activity of hepatic SR-BI. Others have shown that SR-BI is a key, hepatic co-receptor involved in hepatitis C virus infection.
Analysis of mice has established that SR-BI is involved in many mammalian physiologic and pathophysiologic processes, including: maturation, stability and function of blood cells, female fertility, inflammation, thrombosis, responses to infection and apoptosis, movement of lipids into and out of cells, and lipoprotein metabolism, as well as their associated diseases (e.g., atherosclerosis, deep vein thrombosis (DVT), CHD). We have generated SR-BI homozygous null (knockout) mice and exploited their characteristics to generate several novel murine models of fatal occlusive atherosclerotic CHD. These new models appear to be especially attractive for the analysis of the molecular and cellular mechanisms underlying CHD and for developing new pharmacologic and genetic therapies for the prevention and/or treatment of cardiovascular disease. If SR-BI's functions in humans are similar to those in mice, SR-BI will become an attractive target for therapeutic intervention in a variety of diseases.