A receptor-mediated pathway for cholesterol homeostasis.

  title={A receptor-mediated pathway for cholesterol homeostasis.},
  author={M. Scott Brown and Joseph L. Goldstein},
  volume={232 4746},
In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that… 

The LDL receptor in familial hypercholesterolemia: use of human mutations to dissect a membrane protein.

The analysis of four large deletions has revealed an unexpectedly universal involvement of Alu repeats in their generation, and studies indicate that repetitive DNAs can destabilize a gene through homologous recombination.

Rational therapy of familial hypercholesterolemia.

This issue of Circulation, Kume et a17 have used the WHHL rabbit model to use the existence of an animal model for the disease in the form of the Watanabe Heritable Hyperlipidemic (WHHL) rabbit to study the pathogenesis of FH.

Molecular mechanisms of autosomal recessive hypercholesterolemia

The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the β2-adaptin subunit of AP-2.

The LDL Receptor: Structural Insight from Human Mutations

The cell surface receptor for low density lipoprotein plays an important role in the regulation of cholesterol metabolism in humans and animals and is of interest because its expression is regulated at the transcriptional level by a feedback mechanism that is responsive to the level of cholesterol in the cell.

Platelets from genome to proteome and beyond

  • R. Becker
  • Biology
    Journal of Thrombosis and Thrombolysis
  • 2006
Several genetic variants of platelet surface integrins, including GPVI (T13254C polymorphism), GPIIIa (PI), GPIa/IIa and GPIb/IX, with a potential role in thrombosis have been described.

The “CholesteROR” Protective Pathway in the Vascular System

Retinoic acid receptor-related Orphan Receptor &agr; appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression, yet its activity is regulated by cholesterol itself, making ROR&agR; an intracellular cholesterol target.

Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia

The present data suggest that the combination of these clinical features is no longer appropriate for the diagnosis of LDL-receptor-defective FH, but may be a common feature of a defective LDL receptor pathway originating either from defective LDL receptors or from malfunctioning ligand apo B-100.

Familial hypercholesterolaemia: a common disease.

This editorial refers to ‘Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217’, by

Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

The multiple actions of U18666A have enabled major discoveries in lipid research and contributed to understanding the pathophysiology of multiple diseases as well as providing animal models for two important disorders: petite mal (absence) epilepsy and cataracts.



Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol.

  • J. GoldsteinM. Brown
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1973
The demonstration of apparently identical kinetic properties of the reductase activity of control and mutant cells, coupled with the evidence that this enzyme is normally regulated not by allosteric effectors but by alterations in enzyme synthesis and degradation, suggests that the primary genetic abnormality does not involve the structural gene for the enzyme itself, but a hitherto unidentified gene whose product is necessary for mediation of feedback control by lipoproteins.

Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo.

It is suggested that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates.

Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol.

If plasma LDL levels are to be kept low, the activities of the LDL receptor and HMG-CoA reductase must be regulated in a coordinate manner in the body as well as in tissue culture.

Mevinolin stimulates receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.

The current results show that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in FH heterozygotes to produce an increased number of LDL receptors, and raises the possibility that other genetic diseases may be treated through manipulation of regulatory signals that control the rates of synthesis of gene products.

Receptor-mediated low density lipoprotein catabolism in man.

It is concluded that the specific LDL receptor mechanism operates in vivo and probably accounts for 33% and 16% of overall LDL catabolism in normal and heterozygous familial hypercholesterolemic subjects, respectively.

Atherosclerosis: the low-density lipoprotein receptor hypothesis.

Biological synthesis of cholesterol.

Publisher Summary This chapter examines cholesterol metabolism in terms of the molecular events that are responsible for constructing cyclopentanoperhydrophenanthrene derivatives from small molecular