Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor

J. L. Goldstein, J. A S Helgeson, M. S. Brown

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Low density lipoprotein (LDL), the major cholesterol-transport protein in human plasma, binds to specific receptors on mammalian cells and is taken up by receptor-mediated endocytosis and digested in lysosomes, thereby delivering cholesterol to the cells. In the current paper, we establish conditions in which the growth of Chinese hamster ovary (CHO) cells and the Raji line of human malignant lymphoma cells is dependent on the uptake of LDL via the LDL receptor. The drug compactin (ML-236B) was used to inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, thus blocking cholesterol synthesis and making cells dependent on external cholesterol. When CHO or Raji cells were grown in the presence of compactin and in serum from which the lipoproteins had been removed, growth was arrested. Growth was restored by the addition of LDL. This restoration required receptor-mediated uptake of LDL as shown by the following observations: high density lipoprotein, which does not bind to the LDL receptor, did not support growth; acetylation of LDL, which abolishes LDL binding, blocked the ability of LDL to support growth; protamine, which also blocks LDL binding, reduced the ability of LDL to support growth; and a line of Chinese hamster lung cells (V-79 cells), which are deficient in LDL receptors, were resistant to the growth-promoting effects of LDL. The availability of culture conditions in which the growth of cells is dependent on the receptor-mediated uptake of LDL should permit a detailed somatic cell genetic analysis o the LDL receptor pathway for cholesterol homeostasis.

Original languageEnglish (US)
Pages (from-to)5403-5409
Number of pages7
JournalJournal of Biological Chemistry
Volume254
Issue number12
StatePublished - Dec 1 1979

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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