Cholesterol, The Essentials

Cholesterol is an organic sterol, or in other words; a type of lipid molecule that is biosynthesized in all eukaryotic cells. It is an essential structural component to all animal cell membranes to maintain structural integrity and fluidity. Cholesterol allows the membrane to readily change shape in times of stress, as well as protects the cell membrane from exogenous impact in the absence of a cell wall. Not only is cholesterol a cell membrane component, it also serves as a precursor to the biosynthesis of steroid hormones, vitamin D, and bile acids.

Each cell is capable of biosynthesis of cholesterol. It is synthesized via a complex 37-step pathway beginning with the Mevalonate pathway and ending with the conversion of lanosterol to cholesterol via another 19-step pathway. Cholesterol can also be ingested, most commonly in the form of esterified cholesterol, which is poorly absorbed by the body. There is tight regulation between the synthesis of cholesterol and ingested cholesterol so when ingested cholesterol increases, synthesis is down-regulated and vice versa so blood plasma levels of cholesterol reflect this and will not fluctuate much in any. That being said, in the initial hours after ingestion when lipoproteins are transporting the absorbed fats throughout the body, there will be a transient increase in blood plasma levels of cholesterol. Cholesterol can be recycled in the body and the liver excretes the non-esterified form via bile into the digestive tract.

To understand where cholesterol is in the membrane, its important to first understand the basic principle of the phospholipid bilayer, cultivating most of the eukaryotic cells. Phospholipids are amphipathic molecules composed of one glycerol molecule, one phosphate group, and two fatty acid molecules. The glycerol + phosphate head in combination create a hydrophilic head that attracts water molecules because of its negative charge. On the flip side, the fatty acid chains (uncharged) are non-polar and hydrophobic, meaning they repel water molecules.

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The hydroxyl group on cholesterol interacts with the polar acids of the phospholipids while the bulky steroid and hydrocarbon chain interact with the non-polar fatty acids. The steroid interaction with the fatty acids increases membrane “packing”, increasing the resilience and the stability of the membrane, thus eukaryotic cells do not need cell walls such that prokaryotic organisms do.

Biosynthesis starts within the Mevalonate pathway where two molecules of acetyl CoA dimerize to form acetoacetyl-CoA. This molecule further condenses with another acetyl CoA to form 3-hydroxy-3-methyglutaryl CoA, otherwise known as HMG-CoA. HMG-CoA is reduced to mevalonate by the enzyme HMG-CoA reductase. The production of mevalonate is the rate-limiting step in cholesterol synthesis and is the site of action for statins which is a class of cholesterol lowering drugs. Mevalonate is converted to isopentenyl pyrophosphate (IPP) through two phosphorylation steps and one decarboxylation step. Three molecules of IPP condense to form farnesyl pyrophosphate through the enzyme geranyl transferase. In the endoplasmic reticulum two molecules of farnesyl pyrophosphate dimerize to form squalene by action of squalene synthase. Squalene forms lanosterol through oxidosqualene cyclase. Finally in a 19-step process lanosterol is converted to cholesterol.

Previously mentioned the biosynthesis of cholesterol is directly regulated by the levels present. A higher intake of dietary cholesterol reduces endogenous synthesis, whereas lower dietary intake has the opposite effect. Protein sterol regulatory element-binding protein-1 and 2 (SREBP) is the main regulatory mechanism of intracellular cholesterol in the endoplasmic reticulum. When cholesterol is present, SREBP is bound to SREBP cleavage-activating protein (SCAP) and INSIG-1. When cholesterol levels decrease, INSIG-1 dissociates and the SREBP-SCAP complex migrates to the golgi apparatus where SREBP is cleaved by two proteases. The then cleaved SREBP acts as a transcription factor in the nucleus to bind to the sterol regulatory element (SRE). This induces LDLR and HMG-CoA reductase transcription and synthesis. The role of HMG-CoA reductase is in the melavonate pathway and the LDL receptor scavenges any circulating LDL in the bloodstream. Just as cholesterol synthesis can be induced, it can also be repressed via HMG-CoA reductase. The molecule contains a cytosolic domain which is responsible for its catalytic function and also a membrane domain. The membrane domain is essentially the brain of the molecule, it senses incoming signals and processes them. One such signal can be for degradation. Increasing concentrations of cholesterol change the domains oligomerization state which makes it more susceptible to destruction by the proteosome.

Transportation of cholesterol occurs via lipoproteins. There are several types of lipoproteins present in the blood with different densities. In order of increasing density, there are chylomicrons, VLDL, IDL, LDL, and HDL. Cholesterol within the different lipoproteins is identical, although it may be carried as its alcohol form (cholesterol-OH) or as cholesterol esters. Lipoproteins are particles composed of complex apolipoproteins which can be recognized by specific receptors on different cell membranes.

Chylomicrons are the least dense molecule. It contains apolipoprotein B-48, apolipoprotein C, and apolipoprotein E. Chylomicrons carry fat from the intestine to muscle and other tissues in need of fatty acids for energy. Unused cholesterol remains in the chylomicron and taken up by the liver.

VLDL, or very-low-density-lipoprotein molecules are produced by the liver by cholesterol that was not used in the synthesis of bile acids. VLDL contains apolipoprotein B100, and apolipoprotein E and are degraded by lipoprotein lipase on the blood vessel wall to IDL.

Blood vessels can take up triacylglycerol from IDL molecules, increasing the concentration of cholesterol. IDL molecules then undergo one of two fates; either metabolized by HTGL or LIPC or hepatic triglyceride lipase and taken up by the LDL receptor on the hepatocyte surface or they can lose their triacylglycerols in the bloodstream until they become LDL molecules themselves with high levels of cholesterol in them.

LDL molecules are the major blood cholesterol carriers. LDL molecules contain apolipoprotein B100 in small amounts, which is recognized by LDL receptors in peripheral tissues. When LDL binds it forms vesicles within the cell via endocytosis. The vesicles then fuse with lysosomes where the lysosomal acid lipase enzyme hydrolyzes the cholesterol esters. The LAL allows the cholesterol to be taken up for membrane synthesis or esterified and stored within the cell.

During the process of cholesterol absorption by the cell, the LDL receptors are saturated and used up. LDL synthesis is regulated by SREBP, the same protein that regulates cholesterol synthesis. In homeostasis a cell with abundant cholesterol will down-regulate LDL receptor synthesis, and with an absence of cholesterol will up-regulate its LDL receptor synthesis. In cases where LDL receptors become unregulated, LDL molecules are oxidized and taken up by macrophages, which become engorged in walls of blood vessels and contribute to atherosclerotic plaque formation. Theses plaques contribute to heart attacks, strokes and other comorbidities. It is from this that LDL cholesterol is considered to be the “bad” cholesterol.

HDL particles aid in the transportation of cholesterol back to the liver either for excretion or for transport to other tissues that synthesize hormones. Large numbers of HDL particles correlate to better health outcomes.

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Metabolism of cholesterol occurs in the liver and is oxidized into bile acids. These bile acids are conjugated to glycine, taurine, glucuronic acid or sulfate. These bile acids are secreted by the liver with bile. About 95% of the bile acids are reabsorbed from the intestines and the remainder is lost in the feces. The excretion and reabsorption of bile acids forms the foundation of the enterohepatic circulation. This functions in digestion and absorption of dietary fats.

As mentioned before, cholesterol also plays a role in steroidogenesis. Steroidogenesis is the biological process by which steroids are generated. The major classes of steroids include progestogen, corticosteroids such as cortisol, androgens and estrogens. Progesterones are the precursors of all human steroids. All tissues that produce steroids must first convert cholesterol to pregnenolone which is the rate-limiting step is steroid biosynthesis. Cortisol, corticosterone, aldosterone, and testosterone are produced in the adrenal cortex. Estradiol, estrone, and progesterone are made primarily in the ovary. Testosterone is synthesized primarily in the testes.

Cholesterol is very important in many biological pathways and has many essential functions. It is tightly internally regulated because its such an important molecule in the human body. Its no surprise that when that internal regulation fails or the amount of cholesterol in the body is out of balance that there are consequences. Its important to understand the basic principles and that can be the best treatment for any imbalance.

-Caleb

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