Regulation of Cholesterol
The cellular supply of cholesterol is maintained at a balanced level by three distinct mechanisms:
1)Regulation of HMGR, HMG-reductase activity and levels. HMG is the product of condensation of two molecules of Aceto-acetyl-coA in the biosynthesis of cholesterol.
2)Regulation of excess intracellular free cholesterol through the activity of sterol O-acyltransferases, SOAT1 and SOAT2 which is the predominant activity in liver.
3)Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse transport.
The first three control mechanisms are exerted by cholesterol itself. Cholesterol acts as a feed-back inhibitor of pre-existing HMGR as well as inducing rapid degradation of the enzyme. In addition, when cholesterol is in excess the amount of mRNA for HMGR is reduced because of decreased expression of the gene.
-The feedback mechanisms are typical of metabolic pathways, same happens with thyroid hormones, T3 and T4, they act as inhibitors of their own production when levels are too high controlling the release of TSH whose demand decreases in this case and its level goes down; in the opposite way when levels of the hormones are low, there is more demand of production and TSH level goes up.
The thyroid metabolism also influences the cholesterol level, especially while in hypothyroidism, in this case with low levels of thyroid hormones all the metabolic functions are reduced and delayed and therefore there is not metabolization of cholesterol and more accumulation-
Regulation of HMGR through covalent modification occurs because of phosphorylation and dephosphorylation. The enzyme is most active in its unmodified form. Phosphorylation of the enzyme decreases its activity. HMGR is phosphorylated by AMP-activated protein-kinase, AMPK. AMPK itself is activated via phosphorylation. Phosphorylation of AMPK is catalyzed by at least two enzymes.
The activity of HMGR is additionally controlled by the cAMP signaling pathway. Increases in cAMP lead to activation of cAMP-dependent protein kinase, PKA. When the regulatory subunits are phosphorylated by PKA the activity of the associated phosphatases is reduced which results in AMPK remaining in the phosphorylated and active state, and HMGR in the phosphorylated and inactive state.
As the stimulus leading to increased cAMP production is removed, the level of phosphorylation decreases and that of dephosphorylations increases. The net result is a return to a higher level of HMGR activity. In contrast, insulin leads to a decrease in cAMP, which in turn activates cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to inhibit HMGR activity is consistent with the effects of these hormones on other metabolic pathways. The basic function of these two hormones is to control the availability and delivery of energy to all cells of the body.
Long-term control of HMGR activity is exerted primarily through control over the synthesis and degradation of the enzyme. When levels of cholesterol are high, the level of expression of the HMGR gene is reduced. Conversely, reduced levels of cholesterol activate expression of the gene. Insulin also brings about long-term regulation of cholesterol metabolism by increasing the level of HMGR synthesis.
Treatment of Hypercholesterolemia
Reductions in circulating cholesterol levels can have profound positive impacts on cardiovascular disease, particularly on atherosclerosis.
Yet, the statement tests that: “Control of dietary intake is one of the easiest and least cost way to achieve reductions in cholesterol”.
-This assertion, and which is the obvious one contrasts the one stating that “More cholesterol we introduce with diet, less is produced by liver”. But, reasoning they seem both to make sense if we consider the feedback mechanism-
Recent studies in laboratory rats have demonstrated an additional benefit of reductions in dietary cholesterol intake. In these animals it was observed that reductions in dietary cholesterol not only resulted in decreased serum VLDL and LDL, and increased HDL but DNA synthesis was also shown to be increased in the thymus and spleen. Based on histological examination of the spleen, thymus, and lymph nodes it was found that there was an increased number of immature cells and enhanced mitotic activity indicative of enhanced proliferation. These results suggest that a marked reduction in serum LDL, induced by reduced cholesterol intake, stimulates enhanced DNA synthesis and cell proliferation.
Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily pointed at reducing the risk of atherosclerosis and subsequent coronary artery disease that occurs in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if non-pharmacologic interventions like altered diet and exercise have failed to lower plasma lipids.
Statins, the most common therapy, are drugs that inhibits HMG-CoA reductase, HMGR. The net result of treatment is an increased cellular uptake of LDL, since the intracellular synthesis of cholesterol is inhibited, and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate, the product of the HMG-CoA reductase reaction, is required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments bring some risk of toxicity.
It seems that the statins have become recognized as a class of drugs capable of more pharmacologic benefits than just lowering blood cholesterol levels via their actions on HMGR. Part of the cardiac benefit of the statins relates to their ability to regulate the production of anti-inflammatory compounds.
Statins seems to also have some effects on immune function, like attenuation of autoimmune disease, inhibition of T-cell proliferation, inhibition of inflammatory co-stimulatory molecule expression, decreases in leukocyte infiltration, and promotion of a shift in cytokine profiles of helper T-cell types from Th1 to Th2.
Another common drug used now for lowering cholesterol is Nicotinic acid, or Niacin, or vitamin B3. This reduces the plasma levels of both VLDL and LDL by inhibiting hepatic VLDL secretion. In addition, nicotinic acid administration strongly increases the circulating levels of HDL. Unfortunately, is administration is compromised for the unpleasant side-effect of flushing, as strong cutaneous vasodilation.
-These the most common drugs of conventional therapy, but there are more than these-
Alternative Options of Treatments
The natural options for lowering cholesterol are various, I will just mention the most typical elements present in the major number of supplements, and most typical suggestions and tips that can be found online as soon as we look for “natural option, or natural remedies for lowering cholesterol”.
As we all know, diet and exercise are number one priority and essential steps to take for most of the diseases, and fibers, especially soluble fibers, are the most recommended, oat, barley and psyllium are the best, but oat-B-glucans are a specific type of oat that seems to lower the bad cholesterol at particularly good percentage of rate.
Here some of the most typical suggested foods to lower cholesterol.
Niacin, fish oil, CoQ10, garlic, plant sterols and stanols, red yeast rice (the natural version of statins), pantetheine or vitamin B5 analog, olive leaves, bergamot, berberine, choline and phosphatidylcholine, and many more compounds or herbs can be found in different arrangements and assembling in supplements for cholesterol; it depends on the company, some they have more elements, some usually two or three of these mentioned.
What it looks important about mono and polyunsaturated fats, and which are respectively oil of olive and omega’s-3 is that they reduce the oxidation of lipoprotein, the dangerous step toward plaque formation and clogging of arteries, decrease of LDL, and increasing of HDL.
One of the most recommended products online besides the most typical is “Cholesteoff”, made by Nature Made and containing Sterols and Stanols, plus Pantetheine, I believe. I am mentioning because I found some interesting information in regard of soy and so of sterols and seems that they really have been taking always more in consideration.
In this paragraph from a book of Natural Medicine has been examined the influences of soy on cholesterol metabolism; it seems that regular intake of soy foods, especially in place of more common animal protein sources, leads to modest meaningful cholesterol reductions in hypercholesterolemic individuals. Soy’s main mechanisms of action for this appear to be interfering with cholesterol absorption, increasing fecal bile acids excretion, and upregulating low density lipoprotein (LDL) receptor expression.
Individual studies found that hyperlipidemic men and women receiving soy protein with isoflavones in addition to a National Cholesterol Education Program showed significantly lower total cholesterol, estimated coronary artery disease risk, total/high-density lipoprotein (HDL) ratio, LDL/HDL ratio, and apolipoprotein B/A-1 ratio than those using the program and diet alone; LDL cholesterol, apolipoprotein B,, homocysteine, and oxidized LDL levels were also lower with soy than during the program and diet alone.
In a similar study hypercholesterolemic postmenopausal women receiving soy protein and isoflavones in addition to program and diets showed a greater decrease in non-HDL cholesterol than those receiving program and diets alone, and those receiving soy protein and isoflavones also showed increases in HDL cholesterol, as well as decrease in LDL levels.
The results of a 2010 study suggest that soy foods’ potential benefits to lipid profiles may be significantly improved by combination with a prebiotic like inulin. Hyperlipidemic men and women given 30 g soy protein, 61 mg soy isoflavones, and 10 g oligofructose-enriched inulin showed significant improvements in measures of LDL and HDL cholesterol compared with either soy or prebiotic alone.
As for the most today the solutions are different within the same conventional medicine and with the integrative even more; it is always up to us the final decision and what we feel our body can tolerate or not, interferences with other medications or supplements that we already take, and capability of the systems to process everything, mainly gastroenteric and urinary system and even more the liver where everything is processed.
Thanks For Reading.
Textbook of Natural Medicine, 2020, Cheryl Kos ND, by sciencedirect.com
Introductory picture by Healthline.com