Atherosclerosis: The low-density lipoprotein receptor hypothesis

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193 Scopus citations


Recent biochemical, genetic, and ultrastructural studies have disclosed that non-hepatic human cells, such as fibroblasts, lymphocytes, and aortic smooth muscle cells, utilize a specific metabolic pathway, the low-density lipoprotein (LDL) pathway, to supply themselves with cholesterol. The critical component of this pathway is a specific high-affinity receptor on the cell surface that binds LDL, the major cholesterol-carrying lipoprotein of human plasma. Cellular uptake of the receptor-bound LDL is followed by intralysosomal degradation of the lipoprotein with release of its cholesterol for use in cellular membrane synthesis. When the LDL receptor is genetically absent, as in the homozygous form of familial hypercholesterolemia, the degradation of LDL is impaired, the lipoprotein accumulates to very high levels in the plasma, and a severe form of atherosclerosis ensues. In this paper we present the hypothesis that the normal function of the high-affinity cell-surface LDL receptor is to allow non-hepatic cells to supply themselves with cholesterol at a time when the LDL concentration in plasma is maintained at low levels. We then discuss a mechanism by which this hypothesis might explain the widespread occurrence of atherosclerosis in humans with "normal" plasma LDL-cholesterol levels. The data on the LDL pathway lend biochemical support to the conclusion previously derived from epidemiologic studies-namely, that the "normal" plasma level of LDL-cholesterol in Western man is unphysiologically high.

Original languageEnglish (US)
Pages (from-to)1257-1275
Number of pages19
Issue number11
StatePublished - Nov 1977

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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