Cholesterol Metabolism Regulation

Abstract

A complex set of homeostatic mechanisms maintains strict control over the level of free cholesterol within the cell. Disruption of these mechanisms can lead to developmental and/or neurodegenerative disorders as well as increased levels of circulating low‚Äźdensity lipoprotein and an increased risk of coronary artery disease.

Keywords: homeostasis; atherosclerosis

Figure 1.

Regulation of cellular cholesterol homeostasis. Cells acquire cholesterol by biosynthesis from acetate in a series of approximately 30 biochemical steps, and through receptor‐mediated endocytosis of cholesterol‐rich LDL particles. Cells maintain cholesterol homeostasis by regulating cholesterol synthesis, cholesterol esterification, and LDL uptake. Cholesterol biosynthesis and uptake are regulated by the transcriptional control of a number of genes, including 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMGCoA) synthase, HMGCoA reductase, and LDL receptor. Degradation of HMGCoA reductase is enhanced by cholesterol and cholesterol precursors. Finally, cholesterol and oxysterols allosterically activate ACAT, increasing the conversion of free cholesterol into insoluble cholesteryl esters.

Figure 2.

Mechanisms of cholesterol homeostasis. The major mechanisms of cellular cholesterol homeostasis sense the level of cholesterol in the ER and depend upon intracellular sterol transport. SREBP is retained in the ER and its proteolytic activation is inhibited by cholesterol. HMGCoA reductase protein turnover depends on transport of sterols and sterol intermediates to the ER. ACAT also localizes to the ER and is allosterically activated by cholesterol. The majority (90%) of cellular cholesterol resides in the plasma membrane, and the mechanism(s) by which cholesterol and sterol intermediates move to the ER to trigger these events is poorly understood.

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References

Bodzioch M, Orso E, Klucken J et al. (1999) The gene encoding ATP‐binding cassette transporter 1 is mutated in Tangier disease. Nature Genetics 22: 347–351.

Brewer Jr. HB and Santamarina‐Fojo S (2003) New insights into the role of the adenosine triphosphate‐binding cassette transporters in high‐density lipoprotein metabolism and reverse cholesterol transport. American Journal of Cardiology 91: 3E–11E.

Briggs MR, Yokoyama C, Wang X, Brown MS and Goldstein JL (1993) Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter I. Identification of the protein and delineation of its target nucleotide sequence. Journal of Biological Chemistry 268: 14490–14496.

Brooks‐Wilson A, Marcil M, Clee SM et al. (1999) Mutations in ABC1 in Tangier disease and familial high‐density lipoprotein deficiency. Nature Genetics 22: 336–345.

Brown MS and Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proceedings of the National Academy of Sciences of the USA 96: 11041–11048.

Burris TP, Eacho PI and Cao G (2002) Genetic disorders associated with ATP binding cassette cholesterol transporters. Molecular Genetics and Metabolism 77: 13–20.

Carstea ED, Morris JA, Coleman KG et al. (1997) Niemann‐Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277: 228–231 (see comments).

Chang T, Chang C and Cheng D (1997) Acyl‐coenzyme A:cholesterol acyltransferase. Annual Review of Biochemistry 66: 613–638.

Chiang JY (2002) Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocrine Reviews 23: 443–463.

Dawson P, Ridgway N, Slaughter C, Brown M and Goldstein J (1989) cDNA cloning and expression of oxysterol‐binding protein, an oligomer with a potential leucine zipper. Journal of Biological Chemistry 264: 16798–16803.

Dawson PA, Metherall JE, Ridgway ND, Brown MS and Goldstein JL (1991) Genetic distinction between sterol‐mediated transcriptional and posttranscriptional control of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase. Journal of Biological Chemistry 266: 9128–9134.

Doolittle GM and Chang T‐Y (1982) Solubilization, partial purification, and reconstitution in phosphatidylcholine‐cholesterol liposomes of acyl‐CoA:cholesterol acyltransferase. Biochemistry 21: 674–679.

Evans MJ and Metherall JE (1993) Loss of transcriptional activation of three sterol‐regulated genes in mutant hamster cells. Molecular and Cellular Biology 13: 5175–5185.

Gil G, Faust JR, Chin DJ, Goldstein JL and Brown MS (1985) Membrane‐bound domain of HMG CoA reductase is required for sterol‐enhanced degradation of the enzyme. Cell 41: 249–258.

Hampton R and Bhakta H (1997) Ubiquitin‐mediated regulation of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase. Proceedings of the National Academy of Sciences of the USA 94: 12944–12948.

Horton JD, Shah NA, Warrington JA et al. (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proceedings of the National Academy of Sciences of the USA 100: 12027–12032.

Ingham PW and McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes and Development 15: 3059–3087.

Jeong J and McMahon AP (2002) Cholesterol modification of Hedgehog family proteins. Journal of Clinical Investigation 110: 591–596.

Jingami H, Brown M, Goldstein J, Anderson R and Luskey K (1987) Partial deletion of membrane‐bound domain of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase eliminates sterol‐enhanced degradation and prevents formation of crystalloid endoplasmic reticulum. Journal of Cell Biology 104: 1693–1704.

Jira PE, Waterham HR, Wanders RJ et al. (2003) Smith‐Lemli‐Opitz syndrome and the DHCR7 gene. Annals of Human Genetics 67: 269–280.

Lange Y, Swaisgood MH, Ramos BV and Steck TL (1989) Plasma membranes contain half the phospholipid and 90% of the cholesterol and sphingomyelin in cultured human fibroblasts. Journal of Biological Chemistry 264: 3786–3793.

Lu K, Lee MH, Hazard S et al. (2001) Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin‐1 and sterolin‐2, encoded by ABCG5 and ABCG8, respectively. American Journal of Human Genetics 69: 278–290.

Metherall JE, Goldstein JL, Luskey KL and Brown MS (1989) Loss of transcriptional repression of three sterol‐regulated genes in mutant hamster cells. Journal of Biological Chemistry 264: 15634–15641.

Metherall JE, Li H and Waugh KC (1996) Role of multidrug resistance (MDR) P‐glycoproteins in cholesterol biosynthesis. Journal of Biological Chemistry 271: 2634–2640.

Metherall JE, Ridgway ND, Dawson PA, Goldstein JL and Brown MS (1991) A 25‐hydroxycholesterol‐resistant cell line deficient in acyl‐CoA: cholesterol acyltransferase. Journal of Biological Chemistry 266: 12734–12740.

Metherall JE, Waugh KC and Li H (1996) Progesterone inhibits cholesterol biosynthesis in cultured cells: accumulation of cholesterol precursors. Journal of Biological Chemistry 271: 2627–2633.

Nwokoro NA, Wassif CA and Porter FD (2001) Genetic disorders of cholesterol biosynthesis in mice and humans. Molecular Genetics and Metabolism 74: 105–119.

Porter J, Young K and Beachy P (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255–259 (see comments).

Ravid T, Doolman R, Avner R, Harats D and Roitelman J (2000) The ubiquitin‐proteasome pathway mediates the regulated degradation of mammalian 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase. Journal of Biological Chemistry 275: 35840–35847.

Rust S, Rosier M, Funke H et al. (1999) Tangier disease is caused by mutations in the gene encoding ATP‐binding cassette transporter 1. Nature Genetics 22: 352–355.

Sakai J, Nohturfft A, Cheng D et al. (1997) Identification of complexes between the COOH‐terminal domains of sterol regulatory element‐binding proteins (SREBPs) and SREBP cleavage‐activating protein. Journal of Biological Chemistry 272(32): 20213–20221.

Sever N, Yang T, Brown MS, Goldstein JL and DeBose‐Boyd RA (2003) Accelerated degradation of HMG CoA reductase mediated by binding of insig‐1 to its sterol‐sensing domain. Molecular Cell 11: 25–33.

Smart EJ, Ying YS, Conrad PA and Anderson RG (1994) Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. Journal of Cell Biology 127: 1185–1197.

Stocco DM (2001) StAR protein and the regulation of steroid hormone biosynthesis. Annual Review of Physiology 63: 193–213.

Strauss III JF, Kishida T, Christenson LK, Fujimoto T and Hiroi H (2003) START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Molecular and Cellular Endocrinology 202: 59–65.

Suckling KE, Boyd GS and Smellie CG (1982) Properties of solubilised and reconstituted preparation of acyl‐CoA:cholesterol acyltransferase from rat liver. Biochimica et Biophysica Acta 710: 154–163.

Sun H, Smallwood PM and Nathans J (2000) Biochemical defects in ABCR protein variants associated with human retinopathies. Nature Genetics 26: 242–246.

Wang X, Briggs MR, Hua X et al. (1993) Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. Journal of Biological Chemistry 268: 14497–14504.

Yabe D, Brown MS and Goldstein JL (2002) Insig‐2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element‐binding proteins. Proceedings of the National Academy of Sciences of the USA 99: 12753–12758.

Yang J, Brown MS, Ho YK and Goldstein JL (1995) Three different rearrangements in a single intron truncate sterol regulatory element binding protein‐2 and produce sterol‐resistant phenotype in three cell lines. Role of introns in protein evolution. Journal of Biological Chemistry 270: 12152–12161.

Yang J, Sato R, Goldstein JL and Brown MS (1994) Sterol‐resistant transcription in CHO cells caused by gene rearrangement that truncates SREBP‐2. Genes & Development 8: 1910–1919.

Yang T, Espenshade PJ, Wright ME et al. (2002) Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG‐1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489–500.

Yokoyama C, Wang X, Briggs MR et al. (1993) SREBP‐1, a basic‐helix‐loop‐helix‐leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75: 187–197.

Further Reading

Anderson RG, Goldstein J and Brown M (2003) From cholesterol homeostasis to new paradigms in membrane biology. Trends in Cell Biology 13: 534–539.

Gibbons GF, Mitropoulos KA and Myant NB (1982) Biochemistry of Cholesterol. Amsterdam, NY: Elsevier Biomedical.

Goldstein JL, Rawson RB and Brown MS (2002) Mutant mammalian cells as tools to delineate the sterol regulatory element‐binding protein pathway for feedback regulation of lipid synthesis. Archives of Biochemisty and Biophysics 397: 139–148.

Sakai J and Rawson RB (2001) The sterol regulatory element‐binding protein pathway: control of lipid homeostasis through regulated intracellular transport. Current Opinion in Lipidology 12: 261–266.

Yeagle P (1993) The Membranes of Cells, 2nd edn. San Diego: Academic Press.

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Metherall, James E, Nash, Elizabeth A, and Warnick, Darren C(Sep 2005) Cholesterol Metabolism Regulation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0000611]