Cholesterol structure and synthesis

Cholesterol is a type of lipid that is essential for many biological functions in animals. It is a waxy substance that is found in the cell membranes of all animal cells, where it helps to maintain the fluidity and integrity of the membrane. Cholesterol is also a precursor for the synthesis of other important molecules, such as steroid hormones, bile acids, and vitamin D.

The chemical formula of cholesterol is C27H46O. It has a unique structure that consists of three main parts:

• A hydroxyl group (-OH) at one end of the molecule, which is polar and hydrophilic (water-loving). This part can interact with water and other polar molecules.
• A hydrocarbon tail at the other end of the molecule, which is non-polar and hydrophobic (water-fearing). This part can interact with other non-polar molecules, such as fatty acids and triglycerides.
• A sterol nucleus in the middle of the molecule, which is composed of four fused rings of carbon and hydrogen atoms. This part is also non-polar and hydrophobic, and it gives cholesterol its characteristic shape and rigidity.

The structure of cholesterol makes it amphipathic, meaning that it has both polar and non-polar regions. This allows cholesterol to associate with different types of molecules depending on the environment. For example, in aqueous solutions, such as blood plasma, cholesterol can form complexes with proteins called lipoproteins, which have a polar outer layer and a non-polar core. The hydroxyl group of cholesterol can interact with the polar layer, while the hydrocarbon tail and the sterol nucleus can be buried inside the core. This way, cholesterol can be transported in the blood without being dissolved by water.

On the other hand, in lipid bilayers, such as cell membranes, cholesterol can insert itself between the phospholipid molecules that make up the bilayer. The hydroxyl group of cholesterol can align with the polar head groups of the phospholipids, while the hydrocarbon tail and the sterol nucleus can mingle with the non-polar fatty acid chains of the phospholipids. This way, cholesterol can modulate the fluidity and permeability of the membrane by preventing it from becoming too rigid or too fluid.

The structure of cholesterol also determines its biological functions and effects on health. For instance, cholesterol is a precursor for the synthesis of steroid hormones, such as cortisol, aldosterone, estrogen, progesterone, and testosterone. These hormones are derived from cholesterol by modifying its sterol nucleus through various enzymatic reactions. Steroid hormones are involved in regulating many physiological processes, such as metabolism, inflammation, stress response, reproduction, and development.

Cholesterol is also a precursor for the synthesis of bile acids, which are produced in the liver and stored in the gallbladder. Bile acids are secreted into the small intestine to help digest fats and fat-soluble vitamins. They are derived from cholesterol by removing some carbon atoms from its hydrocarbon tail and adding some oxygen atoms to its sterol nucleus. Bile acids are amphipathic like cholesterol, and they can form micelles with fats to make them more soluble in water.

Cholesterol is also a precursor for the synthesis of vitamin D, which is produced in the skin when exposed to sunlight. Vitamin D is derived from cholesterol by breaking one bond in its sterol nucleus and adding a hydroxyl group to another carbon atom. Vitamin D is important for maintaining bone health and calcium homeostasis. It can also modulate immune function and inflammation.

However, too much or too little cholesterol can have negative consequences for health. High levels of cholesterol in the blood can increase the risk of developing atherosclerosis, which is a condition where plaque builds up inside the arteries and narrows them. This can lead to cardiovascular diseases, such as coronary heart disease, stroke, and peripheral artery disease. Low levels of cholesterol in the blood can impair cell membrane function and hormone synthesis. This can lead to neurological disorders, such as depression, anxiety, dementia, and Alzheimer`s disease.

Therefore, it is important to maintain a healthy balance of cholesterol in the body by consuming a balanced diet that includes sources of both dietary cholesterol (such as eggs, meat, cheese) and plant sterols (such as nuts, seeds, grains), exercising regularly, avoiding smoking and excessive alcohol consumption, and managing stress levels. If needed, medications such as statins can also help lower blood cholesterol levels by inhibiting HMG-CoA reductase enzyme that catalyzes an important step in cholesterol synthesis.

In summary,

• Cholesterol is a type of lipid that is essential for many biological functions in animals.
• Cholesterol has a unique structure that consists of a hydroxyl group at one end, a hydrocarbon tail at the other end, and a sterol nucleus in between.
• Cholesterol is amphipathic because it has both polar and non-polar regions that allow it to interact with different types of molecules depending on the environment.
• Cholesterol is a precursor for the synthesis of steroid hormones (such as cortisol), bile acids (such as cholic acid), and vitamin D (such as calcitriol).
• Cholesterol levels need to be balanced in order to prevent health problems such as cardiovascular diseases or neurological disorders.

Cholesterol is a vital component of cell membranes and a precursor for steroid hormones and vitamin D. Cholesterol can be obtained from dietary sources or synthesized de novo by the cells. However, not all cells have the same capacity to produce cholesterol. The location of cholesterol synthesis is mainly determined by the availability of acetyl-CoA, the energy source for the pathway, and the expression of the enzymes involved in the biosynthesis.

According to various sources , cholesterol synthesis takes place in the liver and intestinal mucosa. These organs are major contributors to endogenous production of cholesterol, accounting for about 10% and 15% of total cholesterol synthesis, respectively. The liver and intestine also play important roles in regulating cholesterol homeostasis by secreting bile acids and lipoproteins that transport cholesterol to other tissues or eliminate it from the body.

Other tissues that can synthesize cholesterol include the adrenal cortex, the gonads, the skin, and the brain. The adrenal cortex and the gonads use cholesterol as a substrate for steroid hormone synthesis, such as cortisol, aldosterone, estrogen, and testosterone. The skin converts cholesterol to 7-dehydrocholesterol, which is then converted to vitamin D3 by sunlight exposure. The brain has a high demand for cholesterol for neuronal function and myelination, and it produces most of its own cholesterol since it has a limited uptake of circulating lipoproteins.

Cholesterol synthesis occurs in the cytoplasm and endoplasmic reticulum of the cells. The pathway involves several steps that require different enzymes and cofactors. The rate-limiting enzyme is HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate. This enzyme is regulated by multiple mechanisms, including transcriptional control by sterol regulatory element-binding proteins (SREBPs), post-translational modification by phosphorylation and ubiquitination, and feedback inhibition by cholesterol and its derivatives.

Cholesterol synthesis is an expensive process for cells in terms of energy. It requires 18 molecules of acetyl-CoA, 16 molecules of NADPH, and 36 molecules of ATP to produce one molecule of cholesterol. Therefore, cells need to balance their cholesterol supply and demand by adjusting their synthesis rate according to their needs and environmental factors.

Cholesterol synthesis requires two main substrates: acetyl-CoA and NADPH. Acetyl-CoA is a two-carbon molecule that can be derived from various sources, such as glucose, fatty acids, ketone bodies, and amino acids. NADPH is a cofactor that provides reducing equivalents for the biosynthetic reactions. NADPH can be generated from the pentose phosphate pathway or from the malic enzyme.

The main product of cholesterol synthesis is cholesterol, a 27-carbon molecule with four fused rings and a hydroxyl group. Cholesterol is an essential component of cell membranes, where it modulates fluidity and permeability. Cholesterol is also a precursor for other important molecules in the body, such as bile acids, steroid hormones, and vitamin D.

Besides cholesterol, cholesterol synthesis also produces several intermediate products that have biological functions or serve as precursors for other pathways. Some of these products are:

• Mevalonic acid: a six-carbon molecule that is formed from the reduction of HMG-CoA by HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Mevalonic acid is also a precursor for terpenes, a class of compounds that includes vitamins A and K, coenzyme Q, and carotenoids.
• Isopentenyl pyrophosphate (IPP): a five-carbon molecule that is derived from the phosphorylation and decarboxylation of mevalonic acid. IPP is the basic building block for all isoprenoids, which are molecules with multiple five-carbon units. IPP can also be converted to dimethylallyl pyrophosphate (DMAPP), another five-carbon molecule that can combine with IPP to form larger isoprenoids.
• Geranyl pyrophosphate (GPP): a ten-carbon molecule that is formed from the condensation of IPP and DMAPP. GPP can further react with another IPP to form farnesyl pyrophosphate (FPP), a 15-carbon molecule that can combine with another FPP to form squalene, a 30-carbon molecule that is the precursor for lanosterol and cholesterol.
• Squalene: a 30-carbon molecule that has a linear structure with six double bonds. Squalene is cyclized and oxidized to form lanosterol, a 30-carbon molecule with four rings and one double bond. Lanosterol is then converted to cholesterol by a series of reactions that involve the removal or modification of several methyl groups and double bonds.

Cholesterol is synthesized from cytosolic acetyl-CoA by a sequence of reactions that can be divided into four stages :

• Stage 1: Synthesis of mevalonate from acetyl-CoA. This stage involves three condensation reactions that form a six-carbon compound called β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) from three molecules of acetyl-CoA. The committed and rate-limiting step of cholesterol synthesis is the reduction of HMG-CoA to mevalonate by the enzyme HMG-CoA reductase (HMGCR), which requires two molecules of NADPH as reducing agents. This enzyme is the major target of regulation and inhibition by cholesterol, bile salts, hormones and drugs .

• Stage 2: Conversion of mevalonate to isoprenoid units. Mevalonate is first phosphorylated by ATP and then decarboxylated to form a five-carbon compound called isopentenyl pyrophosphate (IPP). IPP can be isomerized to another five-carbon compound called dimethylallyl pyrophosphate (DMAPP) by the enzyme isopentenyl-diphosphate delta isomerase. These two compounds are the basic building blocks of isoprenoids, a large class of molecules that include cholesterol, terpenes, vitamins A and K, coenzyme Q and dolichol .

• Stage 3: Formation of squalene from isoprenoid units. Six molecules of IPP condense in a head-to-tail fashion to form a thirty-carbon linear compound called squalene. The first step is the condensation of one molecule of IPP and one molecule of DMAPP to form a ten-carbon compound called geranyl pyrophosphate (GPP) by the enzyme geranyltransferase. GPP then reacts with another molecule of IPP to form a fifteen-carbon compound called farnesyl pyrophosphate (FPP) by the enzyme farnesyltransferase. Finally, two molecules of FPP join together to form squalene by the enzyme squalene synthase .

• Stage 4: Cyclization of squalene to cholesterol. Squalene undergoes a series of modifications and cyclization reactions to form the four-ring structure of cholesterol. The first step is the conversion of squalene to squalene epoxide by the enzyme squalene monooxygenase, which requires molecular oxygen and NADPH. Squalene epoxide then cyclizes to form a thirty-carbon sterol called lanosterol by the enzyme lanosterol synthase. Lanosterol is further modified by removal of three methyl groups and rearrangement of double bonds to form cholesterol. This stage involves more than a dozen enzymes and intermediates that are located in the endoplasmic reticulum membrane .

The following figure summarizes the main steps and enzymes involved in cholesterol synthesis:

| Stage | Step | Enzyme | Product |
| --- | --- | --- | --- |
| 1 | 3 acetyl-CoA → HMG-CoA | HMG-CoA synthase | HMG-CoA |
| 1 | HMG-CoA → mevalonate | HMG-CoA reductase | Mevalonate |
| 2 | Mevalonate → IPP | Mevalonate kinase, phosphomevalonate kinase, mevalonate diphosphate decarboxylase | IPP |
| 2 | IPP → DMAPP | Isopentenyl-diphosphate delta isomerase | DMAPP |
| 3 | IPP + DMAPP → GPP | Geranyltransferase | GPP |
| 3 | GPP + IPP → FPP | Farnesyltransferase | FPP |
| 3 | 2 FPP → squalene | Squalene synthase | Squalene |
| 4 | Squalene → squalene epoxide | Squalene monooxygenase | Squalene epoxide |
| 4 | Squalene epoxide → lanosterol | Lanosterol synthase | Lanosterol |
| 4 | Lanosterol → cholesterol | Several enzymes and intermediates | Cholesterol |

Cholesterol synthesis is tightly regulated by various mechanisms to maintain cellular and systemic cholesterol homeostasis. The major regulatory enzyme for cholesterol synthesis is HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid, the committed and rate-limiting step in cholesterol formation . This enzyme is subject to transcriptional, post-transcriptional, translational and post-translational regulation by different factors, such as sterol levels, hormones, drugs and nutrients .

• Transcriptional regulation: The expression of HMG-CoA reductase gene is controlled by a transcription factor called sterol regulatory element-binding protein 2 (SREBP2), which binds to a specific DNA sequence called sterol regulatory element (SRE) in the promoter region of the gene . SREBP2 is synthesized as an inactive precursor that is attached to the endoplasmic reticulum (ER) membrane. When cellular cholesterol levels are low, SREBP2 is cleaved by proteases and released into the cytosol, where it translocates to the nucleus and activates the transcription of HMG-CoA reductase and other genes involved in cholesterol synthesis and uptake . When cellular cholesterol levels are high, SREBP2 remains bound to the ER membrane and its cleavage is inhibited by a feedback mechanism involving sterol-sensing proteins such as SCAP and Insig .
• Post-transcriptional regulation: The stability of HMG-CoA reductase mRNA is also influenced by cellular cholesterol levels. When cholesterol levels are low, HMG-CoA reductase mRNA is stabilized by binding to a protein called SREBP cleavage-activating protein (SCAP), which protects it from degradation . When cholesterol levels are high, SCAP dissociates from HMG-CoA reductase mRNA and allows it to be degraded by nucleases .
• Translational regulation: The translation of HMG-CoA reductase mRNA into protein is also modulated by cellular cholesterol levels. When cholesterol levels are low, HMG-CoA reductase mRNA is efficiently translated by ribosomes . When cholesterol levels are high, HMG-CoA reductase mRNA is poorly translated due to the binding of a small RNA molecule called sterol regulatory element-binding protein RNA (SREBP RNA) to its 5` untranslated region (UTR), which interferes with ribosome binding .
• Post-translational regulation: The activity and stability of HMG-CoA reductase protein are also regulated by several post-translational modifications, such as phosphorylation, ubiquitination and glycosylation . Phosphorylation of HMG-CoA reductase by kinases such as AMP-activated protein kinase (AMPK) and cAMP-dependent protein kinase (PKA) inhibits its activity by reducing its affinity for its substrate HMG-CoA . Phosphorylation is stimulated by hormones such as glucagon and epinephrine that lower cellular energy levels and inhibit cholesterol synthesis . Ubiquitination of HMG-CoA reductase by E3 ubiquitin ligases such as gp78 and Trc8 targets it for degradation by proteasomes . Ubiquitination is enhanced by high cholesterol levels and drugs such as statins that inhibit HMG-CoA reductase activity . Glycosylation of HMG-CoA reductase by N-linked oligosaccharides affects its folding and stability in the ER membrane .

Besides HMG-CoA reductase, another enzyme that is regulated in cholesterol synthesis is squalene monooxygenase, which catalyzes the conversion of squalene to lanosterol, the first cyclized intermediate in cholesterol formation. This enzyme is also controlled by SREBP2-mediated transcriptional regulation and ubiquitin-mediated degradation in response to cellular sterol levels.

In summary, cholesterol synthesis is regulated at multiple levels by different factors that sense and respond to cellular and systemic cholesterol needs. The main regulatory enzyme is HMG-CoA reductase, which is modulated by transcriptional, post-transcriptional, translational and post-translational mechanisms. Another regulated enzyme is squalene monooxygenase, which is influenced by transcriptional and post-translational mechanisms. These regulations ensure that cholesterol synthesis is coordinated with cholesterol uptake, storage and exportation to maintain cholesterol homeostasis.

Cholesterol is a waxy substance that is produced mainly in the liver and intestine, and also obtained from the foods we eat. Cholesterol is essential for building healthy cells, making hormones, and synthesizing vitamin D. However, too much cholesterol in the blood can increase the risk of heart disease and stroke.

Cholesterol and other lipids (fats) are not soluble in water, so they cannot travel freely in the blood. To get around this problem, the body packages cholesterol and other lipids into minuscule protein-covered particles that mix easily with blood. These tiny particles, called lipoproteins (lipid plus protein), move cholesterol and other fats throughout the body .

There are several types of lipoproteins, but the two most commonly known are low-density lipoproteins (LDL) and high-density lipoproteins (HDL) .

• LDL is often called the "bad" cholesterol because it can contribute to the formation of plaque buildup in the arteries (atherosclerosis), which is linked to higher risk for heart attack and stroke . LDL carries cholesterol from the liver to the cells that need it, but if there is more LDL than the cells can use, it can accumulate in the walls of the arteries .
• HDL is often called the "good" cholesterol because it can help remove excess cholesterol from the blood and transport it back to the liver for disposal . HDL also helps prevent LDL from oxidizing and becoming more harmful to the arteries. HDL may also have anti-inflammatory effects that protect the blood vessels.

The balance between LDL and HDL is important for maintaining a healthy cholesterol level. The ratio of total cholesterol to HDL cholesterol is a better indicator of cardiovascular risk than total cholesterol alone. A higher ratio means a higher risk, while a lower ratio means a lower risk. Ideally, the ratio should be below 3.5:1.

The level of cholesterol in the blood is influenced by several factors, such as genetics, diet, exercise, weight, age, gender, smoking, and medications . Some of these factors can be modified by lifestyle changes or medical treatment, while others cannot. The best way to prevent or lower high cholesterol is to eat a healthy diet that is low in saturated fat, trans fat, and dietary cholesterol; exercise regularly; maintain a healthy weight; quit smoking; and take medications as prescribed by your doctor .

Cholesterol is a vital substance for many functions in the body, but it needs to be transported and regulated properly to avoid harmful effects on the cardiovascular system. By understanding how cholesterol circulates in the body and what factors affect its level, you can take steps to keep your cholesterol within a healthy range and lower your risk of heart disease and stroke.

Cholesterol is not only a component of cell membranes, but also a precursor for many important molecules in the body. Some of the functions of cholesterol are:

• Digestion: Cholesterol helps in the production of bile acids, which are essential for the digestion and absorption of fats and fat-soluble vitamins .
• Hormone synthesis: Cholesterol is the starting material for the synthesis of steroid hormones, such as cortisol, aldosterone, estrogen, progesterone and testosterone . These hormones regulate various physiological processes, such as metabolism, blood pressure, reproduction and development.
• Vitamin D synthesis: Cholesterol is converted to 7-dehydrocholesterol in the skin, which is then converted to vitamin D3 by sunlight exposure . Vitamin D3 is essential for calcium homeostasis and bone health.
• Cell signaling: Cholesterol is involved in the formation and function of lipid rafts, which are specialized regions of the cell membrane that facilitate cell signaling and communication .
• Nervous system function: Cholesterol is a major component of myelin, which is the protective sheath that surrounds nerve fibers and enables fast and efficient transmission of nerve impulses .

Cholesterol is vital for many aspects of human health, but it needs to be maintained within a normal range. Too much cholesterol in the blood can lead to atherosclerosis, which is the buildup of plaque in the arteries that can cause heart disease and stroke . Therefore, it is important to monitor and control cholesterol levels through diet, lifestyle and medication if needed.

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