MEDICAL HYPOTHESES AND RESEARCH
VOL. 2, No. 4, October 2005
J. T. Tamsma, et al.  Med Hypotheses Res 2: 567-571.
Metabolic Syndrome and Atherosclerosis: The LDL
Receptor-Related Protein (LRP) Hypothesis
J. T. Tamsma*, L. Hu, B. J. M. van Vlijmen, L. M. Havekes and M. V.
Abstract. The proposed hypothesis will address the pathophysiologic link between the
metabolic syndrome (MS) and atherosclerosis. Visceral obesity is a prominent feature of the
syndrome and has been shown to associate with hepatic insulin resistance. Based on
epidemiologic, clinical and experimental data we propose that the metabolic syndrome if
associated with hepatic insulin resistance results in a dysfunction of the hepatic low-density
lipoprotein receptor-related protein (LRP) clearance pathway. This pathway is responsible
for the clearance and regulation of plasma levels of more than 35 pro-atherothrombotic and
antifibrinolytic proteins. Many of these factors are known to be increased, or to play a role
in MS and diabetes on the one hand, and on atherosclerosis on the other. Examples are
apolipoprotein E, a key apoprotein in the clearance of very low density lipoprotein,
metalloprotease-9 important in plaque vulnerability, and PAI-1 a key regulator of
fibrinolysis. In addition, hepatic LRP deficiency resulted in increased measures of
atherosclerosis in an experimental setting. Dysregulation and accumulation of LRP ligands
in MS-associated hepatic insulin resistance likely is a pathophysiologic link to atherosclerosis.
*Address all correspondence to: Dr. J. T. Tamsma, Vascular Medicine,
Department of General Internal Medicine and Endocrinology, Leiden University Medical
Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands.
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