Cholesterol biosynthesis, regulation and transport (Homo sapiens)

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Cholesterol is an animal sterol that can be found in its free or storage form in plasma, or within body tissues such as the liver, spinal cord and brain. (1) The storage form of cholesterol, known as cholesteryl ester, is formed through an ester bond between a fatty acid carboxylate group and the hydroxyl group of cholesterol. (1)

Cholesterol is essential for the maintenance of stability within animal cell membranes and acts as a precursor for the biosynthesis of Vitamin D and bile acids. (3) It is also necessary for the synthesis of pregnenolone, which in turn, is a precursor for all steroid hormones- including glucocorticoids, estrogens, progesterones, androgens and aldosterone. (3) Another key role of cholesterol is within neuronal physiology; it is essential for synapse and dendrite development, and forms a major component of myelin. (4)

       Biosynthesis and regulation 

Given the essentiality of cholesterol in the body, all cells are capable of its biosynthesis from acetyl-CoA via a complex, multistep process occurring in the endoplasmic reticulum and cytosolic compartments. (1) Generally, over half the cholesterol in the body (approximately 700 mg/d) arises thorough this endogenous biosynthesis, with 20% of this cholesterol being synthesised in the liver and intestine. (1) The remainder is sourced from the consumption of animal-derived foods in the diet. (1) Regulation cholesterol biosynthesis relies on cholesterol levels within the cell. (6)

Maintaining cellular lipid homeostasis is critical for cell survival and homeostatic disturbances may lead to disease. (7) - Membrane bound transcription factors SREBPs (sterol regulatory element binding proteins) regulate de novo cholesterol synthesis. Two genes in the human genome encode 3 SREBP isoforms: SREBP-1a, SREBP 1c/ADD1 and SREBP-2. (6) Activation of SREBPs and thus the biosynthesis of cholesterol is mediated by SCAP (SREBP cleavage activating protein), which acts as a cholesterol sensor in the cell. (6)

- In cholesterol-replete cells, SREBP is bound to SCAP, forming the SREBP-SCAP complex. (6) The complex is bound to Insig, a resident protein on the endoplasmic reticulum whose expression is induced by insulin. (6) Through this sequestration of the SREBP-SCAP complex to the endoplasmic reticulum, cholesterol biosynthesis is inhibited. (6)

- When SCAP senses depleted cholesterol levels within the cell, the SCAP-SREBP complex dissociates from Insig, and moves towards the Golgi apparatus. (6) Two proteolytic cleavage events, mediated by site 1 (S1P) and site 2 (S2P) proteases that are activated by SCAP in low-cholesterol environments, enable the the release of SREBP from the membrane. (6)

- Released SREBP travels to the nucleus and binds to sterol regulatory element (SRE) sequences in target gene promotor regions to stimulate their transcription. (6) Target genes include low-density lipoprotein (LDL) receptor and HMG-CoA reductase. (6) The former plays a key role in scavenging low-density lipoproteins (primary cholesterol carriers) in the blood, while the latter is necessary for endogenous cholesterol synthesis. (6) At the synthesis level, HMG-CoA may also inhibit cholesterol production if the sterol-sensing domain of the enzyme detects cholesterol levels to be high. (6) This is mediated by the sterol-regulated binding of HMG-CoA to Insig, which promotes the enzyme's ubiquitylation and proteosomal degredation. (6)

        Transport 

Cholesterol, predominately in its esterified form, is transported between tissues in lipoproteins. (1) Lipoproteins facilitate the transport of cholesterol and cholesteryl esters via emulsification; i.e. the spherical lipoprotein unit contains a nonpolar core of cholesteryl esters and triglycerides, surrounded by an amphiphathic layer of phospholipids, apoproteins and small amounts of non-esterified cholesterol. (7)

Different types of lipoproteins are classified according to their increasing levels of density. (botham) These include chylomicrons, very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). (7) One or more apolipoproteins (known as Apo A, Apo B, Apo C etc.) are present in each lipoprotein, and contribute to the differentiation, structure and enzymatic activity of the various lipoproteins. (botham) Apolipoproteins also act as ligands for the binding of lipoproteins to tissue lipoprotein receptors, which facilitates the uptake of lipids by cells. (1)

Dietary cholesterol and other lipids, including free fatty acids and triglycerides, are packaged in chylomicrons for transport out of the intestine. (7) Ultimately, triglycerides are transferred to muscle and adipose tissue, and this is followed by the transfer of cholesterol to the liver via chylomicron remnants. (7) Chylomicron remnants, high in cholesteryl esters, are formed following the removal of the lipoprotein’s triglyceride core. (7) The uptake of chylomicron remnants by the liver is facilitated by the binding of Apo E to specific receptors located only on hepatic cells. (7) In the liver, chylomicron remnants are catabolised by lysosomes, leading to the liberation of cholesterol; this cholesterol may either be excreted from the body via bile acids, or incorporated into VLDL for transport alongside biosynthesised cholesterol to peripheral tissues. (7) In the circulation, VLDL is eventually converted into remnant VLDL particles, then into LDL particles, which are cholesterol rich and contain approximately 75% of all plasma cholesterol. (7) It is LDL particles that ultimately bind to specific LDL tissue receptors to provide a supply of cholesterol to peripheral tissues. (6) Such tissues include the adrenal glands, skeletal muscle, lymphocytes, gonads and kidneys. (6)