Cholesterol metabolism

What Is Cholesterol and How Does It Work?

Cholesterol, a type of lipid, is widely found in various tissues of the body. Human gets cholesterol through dietary intake and the body's biosynthesis. Animal sources of egg yolks, meat, and cream are important sources for cholesterol. And cholesterol is mainly synthesized in the liver and intestinal mucous membranes. Cholesterol is a basic component of plasma membranes, and it also can make steroid hormone, vitamin D and bile acids that help digest lipids. Therefore, most tissues need to maintain the right cholesterol supply to keep the metabolic balance of cholesterol.

What Is Cholesterol Metabolism?

Cholesterol metabolism refers to a series of biochemical reactions that occur when cholesterol is synthesized and broken down in the body.

The Function of Cholesterol Metabolism

Normal cholesterol metabolism keeps cholesterol levels in balance, ensuring the survival and normal functioning of the organism.

How Is Cholesterol Metabolized?

Anabolism of Cholesterol:

Cholesterol in the human body mainly comes from endogenous biosynthesis. Cholesterol is primarily synthesized in the endoplasmic reticulum (liver) from acetyl-CoA, one of the metabolites of glucose, fatty acids, and certain amino acids. Endogenous synthetic cholesterol starts from a series of enzymatic reactions in which acetyl-CoA is mediated by HMG-CoA reductase (HMGCR), squalene synthase, squalene monooxygenase, lanosterol synthase, and farnesyl-diphosphate synthase (FPPS).

The cholesterol synthesis pathway is a multi-stage process.

First, two molecules of acetyl-CoA are catalyzed to one molecule of acetoacetyl-CoA by thiolase.

Acetyl-CoA and acetoacetyl-CoA forms HMG-CoA in the action of HMG-CoA synthetase.

The HMG-CoA reductase catalyzes HMG-CoA to generate mevalonic acid (MVA). The process is irreversible. HMG reductase is a rate-limiting enzyme for cholesterol synthesis.

Upon phosphorylation, decarboxylation, and dehydroxylation, MVA is condensed to form squalene.

Squalene produces lanosterol through the catalysis of endoplasmic reticulum cyclase and oxygenase.

Finally, lanosterol is converted to cholesterol through multiple redox reactions.

In addition to the body's synthesis, cholesterol can also be absorbed from the small intestine. The main sources of cholesterol in the intestine are food, bile and shed intestinal epithelial cells. Triglycerides and phospholipids are gradually broken down and digested after the lipids in food are processed by various digestive enzymes in the small intestine, releasing free cholesterol. There is also a large amount of free cholesterol in the bile, which is excreted into the bile by sterol transporter ABCG5 or ABCG8 on the liver membrane. In humans, NPC1L1 (Niemann-pick type C1 like 1), a transmembrane protein, is also expressed on the bile duct membrane and is responsible for re-absorbing cholesterol secreted into bile by the liver.

Catabolism of Cholesterol:

The catabolism of cholesterol is also mainly carried out in the liver. Cholesterol cannot be completely oxidized and decomposed into CO2 and H2O in the body. It is transformed into other compounds containing cyclopentane poly-hydro phenanthrene parent nuclei through oxidation and reduction. And these compounds continue to enter the metabolism process in vivo or are expelled from the body.

Cholesterol is an important component of the cell membrane in the body. Besides, it can also be converted into a variety of substances with important physiological functions. For example, cholesterol can be converted into adrenal cortical hormones and sex hormones such as androgen, estrogen, and progesterone. In the skin, cholesterol can be oxidized to 7-dehydrogenated cholesterol, which is often converted to vitamin D3 by ultraviolet radiation. In the liver, cholesterol can be oxidized into bile acids. And then bile acids flow into the duodenum where they promote the digestion of lipids and the absorption of lipid-soluble vitamins.

In addition to the body's conversion and use of cholesterol, some excess cholesterol is catalyzed to form the cholesterol ester by acetylcholesterol transferase (ACAT) and then stored in the cell. Cholesterol ester transport was mainly mediated by ABCA1 (ATP-binding cassette sub-family A) and ABCG1 (ATP-binding cassette sub-family G member1). Some other cholesterol is directly excreted into the intestinal cavity. And partial cholesterol is assembled as high-density lipoprotein, which later enters to the liver for catabolism. In the lower part of the small intestine, most bile acids are reabsorbed into the liver through the hepatic circulation. The process contributes to the hepatointestinal circulation of bile. A small amount of bile acid is excreted by intestinal bacteria. Besides, the liver can also drain cholesterol directly into the intestine. Cholesterol can also be reduced to sterol fecal by intestinal bacteria. The sterol fecal subsequently is transported out of the body.

Intracellular Transport of Cholesterol

The transport of cholesterol involves both the transport of endogenous cholesterol from the liver to the tissues of the body for use and the transport of cholesterol back to the liver for catabolism.

Cholesterol is transported in the blood as a lipoprotein. Cholesterol combines with apolipoprotein in the blood to form various forms of lipoprotein, such as chylomicron, very-low-density lipoprotein (VLDL), low-density lipoprotein (VLIDL), and high-density lipoprotein (HDL). LDL is mediated by the LDLR into cells. HDL is mediated by scavenger receptor (SR-B1). SR-B1 is related to cholesterol entering and leaving cells and plays an important role in the main signaling pathway of human steroid-producing cells.

Chylomicron: It is responsible for the transport of triglycerides, phospholipids, and cholesterol absorbed by the intestine.

High-density lipoprotein (HDL): It is also known as "good" cholesterol because it mainly transfers cholesterol from tissues other than the liver to the liver for catabolism. Many studies have shown that HDL is a unique type of lipoprotein that "sucks" cholesterol out of the walls of atherosclerotic blood vessels and transports it to the liver for metabolic clearance. Therefore, HDL is honored as"anti-atherosclerotic lipoprotein".

Low-density lipoprotein (LDL): Cholesterol is mainly transported in the blood as LDL-c. LDL transfers cholesterol from the liver to other tissues in the body. Oxidized LDL is one of the risk factors for atherosclerosis. High-level LDL can cause plaque to build up in arteries, so LDL is "bad" cholesterol.

Very-low-density lipoprotein (VLDL): Some people also call VLDL "bad" cholesterol because it causes plaque to accumulates in arteries too. Differently, VLDL carries triglycerides, LDL transports cholesterol.

The Regulation of Cholesterol Metabolism

The main way to maintain the balance of intracellular cholesterol metabolism is a negative feedback regulation of cholesterol synthesis, including transcription level and protein level. Transcription level refers to the regulation of the genes expression of cholesterol synthesis by the SCAP-SREBP pathway in the endoplasmic reticulum. The protein level is the degradation of cholesterol by HMG-CoA reductase (HMGCR).

When intracellular cholesterol level is high, the sterol sensing structure domain (SSD) of SCAP (SREBP cleavage-activating protein) perceives endoplasmic reticulum cholesterol levels and combines with Insig, which causes SREBP/SCAP complexes to be stranded in the endoplasmic reticulum. And then, it inhibits the expression of cholesterol synthesis genes such as HMGCR. On the other hand, lanosterol, the intermediate of cholesterol synthesis, can promote the degradation of HMGCR, thus reducing the synthesis of cholesterol. Cholesterol also can repress the activity of HMGCoA reductase and reduce the synthesis of this enzyme, thereby reducing the synthesis of cholesterol.

When the cholesterol level lows in the cell, SCAP protein conformation changes, and then separates from Insig and assists the SREBP precursor transport from the endoplasmic reticulum to the Golgi apparatus. The SREBP precursor is spliced by S1P (Site-1 protease), S2P (Site-2 protease) existed on the Golgi apparatus, producing nSREBPs with transcriptional activity. nSREBPs transit into the nucleus and activate the expression of downstream related genes of cholesterol synthesis approach by combining sterol regulatory elements, such as LDLR and HMGCR. The increase of LDLR on the cell membrane surface can promote the transport of LDL from plasma to intracellular, thus increasing the level of intracellular cholesterol and reducing the content of plasma LDL. And the increase of HMGCR can facilitate the biosynthesis of cholesterol. This is how cells maintain the homeostasis of cholesterol levels.

Diseases and Cholesterol Metabolism

Cholesterol plays important and multiple physiological roles in cells and is an indispensable component of cell life activities. Therefore, cholesterol must be strictly and precisely regulated to ensure its stable intracellular content. However, the cholesterol level within cells is affected by the dysfunction of cholesterol synthesis, abnormal transportation, and disorganized absorption or excretion, etc. All these factors could lead to various diseases related to abnormal cholesterol metabolism.

Cholesterol is mainly transported in the blood as LDL-C. Macrophages take up excessive LDL lipoprotein particles accumulated on the blood vessel wall. And then HDL transports the cholesterol into the liver for catabolization. When the LDL level is too high to exceed the transport capacity of HDL, the macrophages in the blood vessels will intake large amounts of lipids to form foam cells. Large amounts of foam cells build up in the arterial endothelium to form an uneven distribution of plaque, causing atherosclerosis.

Studies have demonstrated that Huntington's disease is linked to cholesterol metabolism in the brain. By increasing the expression of cholesterol 24-hydroxylase in the brains of Huntington's mice, the mice's neurons shrank, Huntington protein aggregates decreased, and their exercise improved. It also suggests that restoring normal metabolism of cholesterol in the brains of Huntington's patients could be a potential treatment for the disease.

High cholesterol could cause hyperlipidemia, heart attacks, and strokes. If the cholesterol level is too low, many physiological functions cannot be performed normally. So the people will be prone to certain diseases and have a higher prognostic risk of death. Cholesterol metabolism disorder is one of the risk factors of coronary heart disease, Alzheimer's disease, obesity, diabetes, etc.

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