Cholesterol Metabolism Regulation


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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Further Reading

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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. [doi: 10.1038/npg.els.0000611]