HMG-CoA reductase is a glycoprotein that penetrates the ER membrane, the active center of which protrudes into the cytosol

Structure

The major isoform (isoform 1) of HMG-CoA reductase in humans consists of 888 amino acids. It is a polyhedral transmembrane protein (meaning that it possesses many alpha helical transmembrane segments). It contains two main domains:

• conserved N-terminal sterol-sensitive domain (SSD, amino acid range: 88–218). The bound SSD SCAP has been shown to bind cholesterol.[8][9]
• C-terminal catalytic domain (amino acid range: 489-871), namely the 3-hydroxy-3-methyl-glutaryl-CoA reductase domain. This domain is required for proper enzymatic activity of the protein.[10]

Isoform 2 consists of 835 amino acids. This variant is shorter because it lacks an exon in the middle region (amino acids 522–574). This does not affect any of the above domains.

Prevention of excess cholesterol

For modern people, it is important to know that there is no specific prevention for reducing this substance. Therefore it is necessary:

• change your lifestyle;
• give up bad habits (smoking, reducing alcohol consumption);
• eat rationally. Among the diets that doctors prescribe, the Mediterranean diet should be noted. It includes eating plenty of greens, vegetables, fruits, legumes, lean turkey and chicken, and eating lean fish;
• engage in physical exercise. Nordic walking, swimming or walking for more than 2 hours a day helps improve your health.

Exercise helps in lowering cholesterol.
This is what has a positive effect on health and reduces the risk of atherosclerosis, and as a result, such severe socially significant diseases as myocardial infarction, acute cerebrovascular accident and other vascular accidents. It is not for nothing that it is said that doctors treat diseases, but you need to achieve health yourself.

Inhibitors

Drugs

Drugs that inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors (or "statins"), are used to lower serum cholesterol levels as a means of reducing the risk of cardiovascular disease.[11]

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor).[12]Red yeast rice extract, one of the fungal sources , from which statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K or lovastatin (formerly sold under the brand name Mevacor and now available as generic lovastatin).[13]

Vytorin is a combination drug of simvastatin and ezetimibe, which slows the formation of cholesterol in every cell of the body, along with ezetimibe, which reduces the absorption of cholesterol, usually by about 53%, from the intestines.[14]

Statins, HMG-CoA reductase inhibitors, can lower cholesterol and reduce heart disease. However, there is controversy over whether statins may increase the risk of new-onset diabetes mellitus (NOD). Experiments have shown that glucose and cholesterol homeostasis are regulated by statins. HMG-CoA reductase (HMGCR) converts HMG-CoA to mevalonic acid. Thus, when HMGCR activity decreases, cell-bound cholesterol also decreases. This leads to activation of SREBP-2-mediated signaling pathways. Activation of SREBP-2 for cholesterol homeostasis is critical for low-density lipoprotein receptor (LDL) activation (LDLR). The removal of LDL particles from the circulation is enhanced when the amount of LDL in hepatocytes increases. By removing atherogenic lipoprotein particles such as LDL and medium-density lipoprotein, HMGCR inhibitors have been shown to be effective in reducing cardiovascular disease from the circulation, resulting in a reduction in LDL cholesterol levels. Many studies have shown lipophilic statins to be more diabetogenic, possibly because they can easily diffuse into cells and inhibit the production of isoprenoids, which become more potent. Although statins have been shown to be beneficial for cardiovascular disease, there are concerns about an increased risk of new-onset diabetes mellitus (NOD). In addition, statins have also been shown to alter glucose levels. [15]

Hormones

HMG-CoA reductase is active when blood glucose levels are high. The main functions of insulin and glucagon are to maintain glucose homeostasis. Thus, by controlling blood sugar levels, they indirectly affect the activity of HMG-CoA reductase, but the decrease in enzyme activity is caused by AMP-activated protein kinase,[16] which responds to increased AMP concentrations, as well as leptin

What is cholesterol for?

It is important to note that it is vital for a living organism. This substance is included as a material for building the cell wall. The higher its content, the denser the wall and the more capable of survival, which generally has a beneficial effect on the human body. It also protects against cell destruction by free oxygen radicals. Contained in the skin, and under the influence of solar ultraviolet rays it is converted into vitamin D, which, in turn, is necessary for calcium metabolism.

In the liver, bile acids are formed from cholesterol, which are used for the absorption and breakdown of fats in the small intestine. More than 80% of this substance is formed daily in the body, the remaining percentage comes with food.

With a decrease in dietary intake, men experience a decrease in sexual activity, and women experience amenorrhea (absence of menstruation). In addition, with a strict hypocholesterol diet in women of reproductive age, the likelihood of pregnancy is reduced.

Cholesterol is an essential component for myelinated fibers in the brain and is also required for serotonin receptors. Serotonin is responsible for a good mood and ensuring favorable conditions for the functioning of the brain.

Cholesterol is necessary for favorable conditions for brain function.

Clinical significance

Because the reaction catalyzed by HMG-CoA reductase is the rate-limiting step in cholesterol synthesis, this enzyme represents the single major target of current cholesterol-lowering drugs in humans. The medical importance of HMG-CoA reductase continues to expand beyond its direct role in cholesterol synthesis following the discovery that statins may provide cardiovascular benefits independent of cholesterol reduction.[17] Statins have been shown to have anti-inflammatory properties,[18] most likely as a result of their ability to limit the production of key downstream isoprenoids that are essential for parts of the inflammatory response. It may be noted that blocking isoprenoid synthesis with statins has shown promise in the treatment of a mouse model of multiple sclerosis, an inflammatory autoimmune disease.[19]

HMG-CoA reductase is an important developmental enzyme. Inhibition of its activity and the concomitant absence of isoprenoids that provide the exit can lead to defects in germ cell migration.[20] as well as intracerebral hemorrhage.[21]

What drugs lower cholesterol?

Only a doctor can correctly assess the content of this substance and lipoproteins when prescribing laboratory tests. Blood is taken from a peripheral vein to determine the level of low and high density lipoproteins, triglycerides, and cholesterol. The drugs described in the article can only be prescribed by a specialist. The information is provided for informational purposes only.

Statins

The first group is for lowering cholesterol levels. The action of these drugs is aimed at reducing the synthesis of cholesterol in the liver by suppressing the activity of HMG-CoA reductase. With a decrease in cholesterol concentration, the number of receptors for low-density lipoproteins on the surface of liver cells increases, which affects the decrease in the amount of the cholesterol-LDL complex. Statins have a strong evidence base, with many clinical studies showing greater benefits from taking these drugs than the risk of complications with constant use. This group of drugs is the first line in the fight against atherosclerosis. They are also prescribed to prevent unfavorable vascular situations - myocardial infarction, thrombosis, stroke.

Statins are prescribed to prevent vascular pathologies.

Examples of such drugs are:

• Crestor;
• Atoris;
• Livazo;
• Mertenil;
• Liprimar.

Bile acid sequestrants

The mechanism of action is to reduce the absorption of cholesterol in the intestinal lumen. The earliest drugs are cholestyramine and colestipol, resins that bind bile acids to cholesterol in the intestine. These drugs are not absorbed into the systemic circulation and their effect is indirect.

Cholesterol absorption inhibitors

The essence of the interaction of these drugs with cholesterol is to block its absorption in the intestine. However, the drugs do not affect the absorption of other fat-soluble substances.

An example of this group is Ezetrol.

Omega 3 fatty acids

These drugs reduce the concentration of low-density lipoproteins, but the mechanism of their action is poorly understood.

A representative of this group of drugs is Omacor.

A nicotinic acid

This drug is associated with an increase in the level of “good” cholesterol by partially breaking down through an increase in the specific substance apoA1 in liver tissue. The drug has shown its effectiveness in clinical studies (Nicotinic acid tablets).

Regulation

HMG-CoA reductase-Substrate complex (blue: Coenzyme A, red: HMG, green: NADP)
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.

Transcription

Transcription reductase gene is enhanced by sterol regulatory element binding protein

(SREBP).
This protein binds to the sterol regulatory element
(SRE) located at the 5′ end of the reductase gene after controlled proteolytic processing. When SREBP is inactive, it is tethered to or attached to the nuclear membrane by another protein called SREBP cleavage-activating protein (SCAP). SCAP senses low cholesterol concentrations and transports SREBP to the Golgi membrane, where sequential proteolysis by S1P and S2P cleaves SREBP to the active nuclear form, nSREBP. nSREBPs migrate into the nucleus and activate transcription of SRE-containing genes. The nSREBP transcription factor is short-lived. When cholesterol levels rise, Insigs retains the SCAP-SREBP complex in the ER membrane, preventing its incorporation into COPII vesicles.[22][23]

Translation

Translation from mRNA is inhibited by the mevalonate derivative, which is reported to be the isoprenoid farnesol,[24][25] although this role is disputed.[26]

Degradation

Increasing sterol levels increases the susceptibility of the reductase enzyme to ER-associated degradation (ERAD) and proteolysis. Helices 2–6 (of the entire transmembrane domain of HMG-CoA reductase are thought to sense elevated cholesterol levels (direct sterol binding to the SSD of HMG-CoA reductase has not been demonstrated). Lysine residues 89 and 248 can be ubiquinated by ER-resident E3 ligases. The identity of the multiple E3 ligases involved in HMG-CoA degradation is controversial, with proposed candidates being AMFR,[27] Trc8,[28] and RNF145[29][30] The involvement of AMFR and Trc8 is disputed.[31]

Phosphorylation

Short-term regulation of HMG-CoA reductase is achieved by inhibition of phosphorylation (from serine 872, in humans[32]). Decades ago, a cascade of enzymes was thought to control HMG-CoA reductase activity: HMG-CoA reductase kinase was thought to inactivate the enzyme, and the kinase was in turn activated by phosphorylation by HMG-CoA reductase kinase. kinase. An excellent review of mevalonate pathway regulation by Nobel laureates Joseph Goldstein and Michael Brown adds specifics: HMG-CoA reductase is phosphorylated and inactivated by AMP-activated protein kinase, which also phosphorylates and inactivates acetyl-CoA carboxylase, the rate-limiting enzyme in fatty acid biosynthesis.[33] Thus, both pathways using acetyl-CoA for lipid synthesis are inactivated when the energy charge in the cell is low and the AMP concentration is high. A large number of studies have been conducted to identify the upstream kinases that phosphorylate and activate AMP-activated protein kinase.[34]

More recently, LKB1 was identified as a putative AMP kinase kinase,[35] which appears to be associated with calcium/calmodulin signaling. This pathway likely transforms signals from leptin, adiponectin and other signaling molecules.[34]

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