CHOLESTEROL HOMEOSTASIS

CHOLESTEROL HOMEOSTASIS

1. The cholesterol is a non-polar organic lipid that is biosynthesized by the body, as it is an important precursor used for the production of steroid hormones, bile acid and vitamin D, and it´s a component of most human and animal cell membranes. Its homeostasis is vital for the proper cellular and systemic function of the organism, as both its excess and lackness can cause neurodegenerative and cardiovascular diseases, along with other health issues such as cancer

   • Cholesterol homeostasis involves the regulation of its biosynthesis, transport, metabolism, absoprtion and excretion.

2. BIOSYNTHESIS

   • The cholesterol biosynthesis is known as the mevalonate pathway, and consists of five main steps that take place in the liver cells, but can also occur in the intestine, reproductive organs and some glands, and stars with the mevalonate synthesis from two molecules of acetyl-CoA
     • Then, the mevalonate Mevalonate is converted into isopentenyl pyrophosphate that is an isoprenoid unit obtained through two phosphorylation steps and one decarboxylation step that requires ATP.
       • The isopentenyl pyrophosphate in condensed by the enzyme geranyl transferase to form farnesyl pyrophosphate, which subsequently condenses to produce squalene by the action of the enzyme squalene synthase
         • The enzyme oxinosqualene cyclase ciclizes the squalene to form lanosterol
           • And last, the lanosterol is converted into cholesterol through several reactions of reduction, transfer and removal of carbons mediated by NADH and NADPH
   • The cholesterol biosynthesis is regulated by the liberation of the sterol regulatory element-binding protein (SREBP) that works as a transcriptional factor that leads to the production of cholesterol. When the cholesterol levels are low, the SREBP is activated in order to increase the cholesterol. There are two isoforms of SREBP: SREBP 1 and SREBP 2. SREBP 1 regulates genes that stimulate the cholesterol production and increases the induction of lipogenesis, which facilitates the storage of fatty acids as triglycerides. The SREBP 2 controls the net production of cholesterol, increasing it when needed, as it stimulates the transcription of sterol-regulated genes.

3. TRANSPORT

   • The cholesterol must be transported by the lipoproteins, as it can flow through the bloodstream as it is non water-soluble
     • CHYLOMICRONS
       • These are the least dense cholesterol lipoproteins. They carry fatty acids and lipids to the muscle and other tissues, and are degraded by the lipoprotein lipase along the bloodstream until it arrives to the liver as more cholesterol-rich remnants.
     • VERY LOW DENSITY LIPOPROTEINS (VLDL)
       • Once cholesterol is in the liver, it is used to produce bile acids. However, the VLDL are produced by the liver from triglycerides and the cholesterol that wasn´t used in the production of bile acids. Then, the VLDL are liberated into the bloodstream, where their triglyceride content is absorbed by tissues and arteries by the action of the lipoprotein lipase. As triglycerides are absorbed from the VLDL, it starts to convert into more cholesterol-dense lipoproteins known as LDL
     • LOW DENSITY LIPOPROTEINS (LDL)
       • These are the major cholesterol transporters in the body. The cholesterol carried by LDL can be used by the extra-hepatic tissues for the membrane biosynthesis. This lipoprotein is also associated with the "bad" cholesterol, as is the most likely to form plaque that contributes to the development of cardiovascular diseases and atherosclerosis
     • HIGH DESNTITY LIPOPROTEINS (HDL)
       • These transport back the cholesterol to the liver, but also to other tissues to produce hormones or for its excretion. This process in known as reverse cholesterol transport

4. METABOLISM

   • The main metabolic role of the cholesterol, besides being part of the cell membrane and the production of bile acid, is the biosynthesis of steroid hormones
     • The biosynthesis of steroid hormones starts with the transformation of cholesterol into steroids, that will subsequently get converted into the respective hormones of every respective tissue. There are five types of steroid hormones in the human body
       • PROGESTAGENS
         • They are secreted during the pregnancy, and regulate all kind of processes related to it. For example, the progesterone. These are secreted by the ovary
       • GLUCOCORTICOIDS
         • Stimulates the gluconeogenesis and supress inflammation. For example, the cortisol. These are secreted by the adrenal gland
       • MINERALOCORTICOIDS
         • Regulates the ionic balance of Na+, K+ and Cl- in the kidneys. For example, the aldosterone. These are secreted by the adrenal gland
       • ESTROGENS
         • These are the femenine sex hormone that regulates the developement of the female reproductive system and the secondary sex characteristics. For example, estradiol. These are secreted by the ovary
       • ANDROGENS
         • These are the masculine sex hormone that regulates the developement of the male reproductive system and the secondary sex characteristics. For example, testosterone. The are secreted by the testicles

5. EXCRETION

   • The cholesterol is oxidized into bile acids, which subsequently are used to produce the bile. The 50% of the total cholesterol present in the bile is reabsorbed by the small intestine, along with some bile acids. The rest is excreted through the feces

6. There are many diseases related to cholesterol, the steroid hormones and some enzymes that are steroid dependent

   • HYPERCHOLESTEROLEMIA
     • It occurs due to the excess of cholesterol in the body. This leads to atherosclerosis, cardiovascular diseases (increasing the risk of a heart attack and a cerebrovascular accident). The high concentrations and accumulation of LDL are the main cause of the hypercholesteromia. but the low concentration of HDL, which cleans the plaque produced by the LDL, can also contribute to this disorder. The treatments are medication, and a modification of the patients diet in order to reduce the quantity of LDL and increase the HDL. The low risk concentration of cholesterol is below 200 milligrams per deciliter of blood. When this levels are higher than 200, the patient has risk of developing diseases related with the hypercholesterolemia
       • Hypercholesterolemia can also be related to genetic defects, like occurs in the Niemann-Pick type C disease, which promotes the cholesterol accumulation within lysosomes, which lead to neurodegeneration and enlargement of the liver and the spleen, which can lead to more severe health issues
   • HYPOCHOLESTEROLEMIA
     • This disease relates with abnormally low levels of cholesterol, which can lead to depression, and can cause cancer if it´s not treated in time. Hypocholesterolemia is mainly a consequence of other diseases, such as Smith–Lemli–Opitz syndrome, which is a genetic defect that doesn´t allow the correct biosynthesis of cholesterol. Hyperthyroidism, and other endocrine disorders can also cause hypocholesterolemia, as it upregulates the LDL receptors which causes low plasma cholesterol levels
   • HORMONE-RELATED DISEASES
     • These are disorders that relates with the excess or lackness of a hormone in the body. Depending on the type, there can be many consequences in the patient
       • ESTROGENS
         • The excess of estrogens in men can cause the malfunction of their sexual organs, as well as altered humour and infertility, and in women, it can cause breast and uterine cancer, as well as premenstrual syndrome and headaches. It lackness in women is normal in old ages due to the menopause, and it can lead to humoural changes like anxiety or depression. In younger women, it can cause deficient ovulation and menstruation, Turner syndrome and sexual malfunction
         • ANDROGENS
           • The excess of androgens in men can cause violent and aggressive tendencies, cardiovascular diseases, and enlargement of the protate, which can lead to protate cancer and urinary problems; In women it can cause the developement of masculine characteristics along the body, as well as cardiovascular diseases and sexual malfunction
           • GLUCOCORTICOIDS AND MINERALOCORTICOIDS
             • The adrenal cortical insufficency leads to the addison disease which is a consequence of a damage in the suprarrenal gland and the lackness of hormones like cortisol. The symptoms are fatigue, sexual malfunction, muscular pain, ataxia, hyperpigmentation of the skin (which turns it darker), etc. The excess of corticoids, specially cortisol, leads to the cushing syndrome, which causes obesity, deep stretch marks, bruising prone skin, etc. The treatments for both diseases consist of hormonal therapies that help regulate the corticoid levels in the body
             • PROGENTAGENS
               • This affects mainly the women. The decrease of normal levels of progentagens can produce fertility problems, ectopic pregnancy or spontaneous abort (in case of pregnancy). In the other hand, excessive levels of progentagens can produce ovaric cysts, over-estimulation of the adrenal glands, and ovarian and uterin cancer. However, there are some contraceptives which mechanism is to keep the progentagens levels high, as if the women was pregnant, but this levels are not excessive or harmful for the person using this kind of methods.
   • ENZYME (And other hormones) RELATED HORMONAL DEFFICENCIES
     • There are some enzymes that can be altered due to genetic deffects or other factors. This can result in a hormone defficency, which can produce some other health issues
       • 17 ALPHA HYDROXYLASE
         • 21 ALPHA HYDROCYLASE
           • ACTH
             • The excess of this hormone leads to the overproduction of testosterone in both sexes, which contributes to the developement of masculine characteristics in the women
           • The excess of this enzyme inhibits the glucocorticoids and mineralocorticoids synthesis, and it leads to the overpoduction of testosterone in both sexes
         • The lackness of this enzyme doesn´t allow the cortisol, and the sexual hormones to be produced, which can result in the lack of sexual development

7. The cholesterol homeostasis is mediated by sterol-dependant compounds that emit signals that can stimulate or inhibit processes that lead to the regulation of cholesterol quantities in the body

   • The lanosterol (obtained from mevalonate pathway), oxysterol (obtained from cholesterol oxidation) and geranylgeraniol (obtained from mevalonate pathway) can emit a signal that stimulates the HMGCR degradation. HMGCR (HMG-CoA reductase) is one of the main enzymes that controls the mevalonate pathway, and its degradation prevents it from performing its action in this process, which at the same time prevents the mevalonate pathway to be completed, resulting in the decreasement of the cholesterol biosynthesis
   • The cholesterol itself can emit a signal that stimulates the SM degradation and the SREBP pathway inactivation. The SM (sphingomyelin) is an important mediator of the mevalonate pathway, and its degradation will prevent this process to keep going, which will reduce the cholesterol biosynthesis. The inactivation of the SREBP pathway will prevent the mevalonate pathway to even start, and will decrease the cholesterol biosynthesis and long term (relatively) its uptake, but increase its efflux back to the liver. The cholesterol can also emit a signal along with the oxysterols, that will lead to the ACAT activation, which will start the esterification, which prevents the cholesterol accumulation in the body by utilizing it
   • The desmosterol (a compound similar to the cholesterol that can bi used to its biosynthesis), along with the oxysterol emit signals that activate the LRX (Liver X receptor), which inhibits the cholesterol biosynthesis and stimulates its uptake back to the liver

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