How To Trap Heart Attack-Inducing Lipoproteins In The Blood

Atherosclerosis is a disease of the blood vessels that causes many problems, including heart attacks. It is caused by a buildup of fat (lipid)-containing macrophages (the rubbish-collecting cells of the immune system) in the arteries. The presence in the blood of high levels of remnant lipoproteins, cholesterol-rich particles that are produced as the large lipoprotein complexes that transport lipids around the body are degraded, potently promotes the development of atherosclerosis. Therefore, understanding the mechanisms by which lipoprotein remnants are removed from the circulation is an area of intensive research and two studies appearing in the January issue of the Journal of Clinical Investigation provide new insights into these mechanisms.



Jeffrey Esko and colleagues from the University of California in San Diego show that in mice, under normal physiological conditions, molecules known as heparan sulphate proteoglycans on the surface of cells in the liver have a crucial role in removing remnant lipoproteins generated in both the intestine and liver from the blood. However, Helen Hobbs and colleagues show that mice lacking an adaptor protein (ARH) that associates with the receptor for bad cholesterol (LDL) are better at clearing remnant lipoproteins than mice lacking the LDL receptor (LDLR) itself. This indicates that the LDLR is important for remnant lipoprotein clearance under certain circumstances, but whether clearance is mediated directly or indirectly was not determined. Similarly, humans with a mutation in the gene encoding ARH (who suffer from autosomal recessive hypercholesterolemia) are able to clear remnant lipoproteins from the blood, whereas individuals with mutations in their genes encoding the LDLR (who suffer from familial hypercholesterolemia) are not.



In an accompanying commentary, Robert Mahley and Yadong Huang from the Gladstone Institute of Cardiovascular Disease discuss how these complex studies enhance our understanding of lipid clearance from the body and suggest that heparan sulfate proteoglycans might be "responsible for remnant [lipoprotein] uptake by hepatocytes in the presence of defective LDLR internalization."



TITLE: Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members



AUTHOR CONTACT:



Jeffrey D. Esko

University of California, San Diego, La Jolla, California, USA.



Joseph R. Bishop

University of California, San Diego, La Jolla, California, USA.



RELATED MANUSCRIPT



TITLE: Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia



AUTHOR CONTACT:



Helen H. Hobbs

University of Texas Southwestern Medical Center, Dallas, Texas, USA.



Jonathan Cohen

University of Texas Southwestern Medical Center, Dallas, Texas, USA.



TITLE: Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing



AUTHOR CONTACT:



Robert W. Mahley

Gladstone Institute of Neurological Disease, San Francisco, California, USA.







JCI table of contents: January 2, 2007



Contact: Brooke Grindlinger


Journal of Clinical Investigation