Cholesterol

1769:

For the first time, a French doctor isolated cholesterol from gallstones and later from various animal tissues. PMID: 9478044

1815:
It was rediscovered and named the compound “cholesterine”.PMID: 9478044 PMID: 20467214 PMCID: PMC2798703

1856:

1. The concept of cholesterol began to take shape.
2. The atherosclerotic plaque was discovered to be the fundamental cause of atherosclerosis.PMID: 9478044

1888:
The molecular structure of cholesterol was described due to a case report on sudden cardiac death of an 11-year-old child.PMID: 15547293

1900:

1. While investigating whether an excess of protein in the diet was toxic and accelerated the aging process, Adult rabbits developed atherosclerosis after feeding large amounts of meat, eggs, and milk.PMID: 15102877 PMID: 23914012
2. Plaques in aortas from atherosclerosis patients contained 20 times more cholesterol than normal aortas.PMID: 20467214 PMCID: PMC2798703 PMID: 16227628
3. The first experimental was done in the production of atherosclerosis by feeding pure cholesterol to rabbits, thus eliminating proteins. However, similar experiments failed in dogs and rats. After 35 years, it came to know that dogs and rats, unlike rabbits, are quite efficient in converting cholesterol into bile acids.PMID: 20467214 PMCID: PMC2798703
4. In the 1913, the “Lipid Hypothesis” emerged, suggesting a link between cholesterol levels in the blood and heart disease, which led to the understanding that dietary cholesterol intake can raise blood cholesterol levels.PMID: 27474223 
5. In the 1929,lipoproteins discovered.PMC2798703 PMID: 27474223
6. In the 1950,Lot of Epidemiological studies emerged including the famous  “Seven Countries Study” (Japan, Finland, the Netherlands, Yugoslavia, Italy, Greece, USA) by Dr.Ancel Keys also enzyme lipoprotein lipase, discovered. PMC2798703 PMID: 16227628 PMID: 15995167
7. It became clearer that there was an association between lipoproteins and cardiovascular disease.
8. In 1951,During and after World War II, after getting noticed that cholesterol is the precursor of hormones, everybody was eager to synthesize cholesterol.PMCID: PMC2798703
9. Dietary intervention studies started that lowering cholesterol in diet was beneficial. PMID: 15547293 PMID: 32631832
10. In 1953, Michael Oliver started an anti-cholesterol campaign with Sir John McMichael. Later, after the study in 1994, Michael Oliver changed his mind and became a promoter.PMID: 19042967
11. In 1959, an inhibitor of cholesterol biosynthesis ‘STATIN’ a powerful inhibitor of HMG-CoA reductase was tested in rats and dogs. Serious side effects in animals (cataract, hair loss, lymphomas, cancer, rhabdomyolyse (muscles which leads to muscle death), deaths) were not reported; in 1963, a lawsuit was the end of this scandal.DOI:https://doi.org/10.1194/jlr.R600009-JLR200 PMID: 20467214
12. In 1959, apolipoprotein A, B and C identified.PMID: 27474223  
13. In the 1960, studies started showing an association between elevated cholesterol levels and an increased risk of heart disease.
14. In 1961, the American Heart Association recommended reducing dietary fat, limiting their dietary cholesterol intake to 300 milligrams per day, calorie intake and substituting saturated by polyunsaturated fats.
15. In the 1970 development of cholesterol-lowering medications, particularly statins, began.
16. In 1973,Nicotinic acid (Niacin, Vitamin B3) discovered. PMCID: PMC2798703
17. In 1974, scientists showed that human cultivated (vitro study) fibroblasts can attach to LDL and stop HMG-CoA reductase from working. They also found out that the LDL receptor is needed for cells to take up LDL.PMID: 15995167 PMID: 9478044
18. In 1979, the oxidative modification hypothesis was established. Its hypothesis states that the increase in cholesterol content in macrophages is attributed to the endothelial cell-modified LDL, which is oxidized and subsequently metabolized, resulting in Chemotaxis, the movement of an organism or entity in response to a chemical stimulus. PMID: 15995167

The “cholesterol wars” started in the 1950, peaked in the 1970, and weakened in the 1990.PMID: 19042967

1980:

1. Cholesterol content in foods became a focus of nutrition education.
2. Dietary guidelines began to reduce saturated fat and cholesterol intake to lower the risk of heart disease.
3. It has been recommended that saturated fatty acid (SFA) intake be limited to <10% of total calories as a means of reducing risk for cardiovascular disease (CVD).PMID: 29899124
4. Important roles of Cholesterol in the body.

1990:

1. Added complexity to the understanding of cholesterol’s studies into the different subtypes of LDL cholesterol, particularly small, dense LDL particles.
2.  High blood cholesterol is not the only risk factor for heart disease.

2000:

1. Studies highlighted the role of inflammation in atherosclerosis.
2. New treatments for high cholesterol are developed.
3. In 2002, an intestinal cholesterol absorption inhibitor discovered.

Present day:

1.  With ongoing studies, the cholesterol controversy continues to evolve.
   Sir William Osler said: “The good physician treats the disease; the great physician treats the patient who has the disease”.

Summary:
In the early 1900, scientists discovered a link between cholesterol and vascular damage atherosclerosis, but many leading scientists did not consider its importance by thought it to be a natural and unavoidable component of aging. Later on, discovering cholesterol transportation in the blood stream, identifying HDL and LDL and large scale clinical studies showed an important relationship between the dietary fat and heart disease, a “lipid hypothesis” was established. These gave rise to fat-free or low fat dietary guidance, good and bad cholesterol, manufacturers producing low-fat products and medications.

Yet, the reaction of scientists was still mixed.

Additional Reading

The Journal of Lipid Research’s thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: Part I; Part II; Part III; Part IV;Part V

The Donald S. Fredrickson Papers

Trial puts niacin—and cholesterol dogma—in the line of fire

The Cholesterol Wars: The Skeptics vs the Preponderance of Evidence

Etymology:

“cholesterol” is derived from two Greek words ”Chole” means “bile” and Stereos” word means “solid”. It is soft waxy fats.
The name cholesterol comes from bile, which shows that it is in the digestive fluid and that it plays a role in fat metabolism.PMID: 19636418
It is the precursor of bile acid.

NOTE:Not all fats (Omega-3,6) are cholesterol, but all cholesterol is fat.

80% of total daily cholesterol production occurs in the liver and the intestines, normally about 2g depending on dietary intake. It is stored in the liver and the adrenal glands in high concentration and found only in animals and not plants.
The brain and the reproductive organs also produce at higher rates.
Plants have phytosterol and β-sitosterol, and yeast (fungus) have Ergosterol, which plays a similar role like cholesterol.

When a child is young, most of the cholesterol in their body comes from food. This is because the body organs doesn’t make enough cholesterol by itself (endogenous). Hence, breast milk does not only contain cholesterol, but it is also having higher content compared to kid formula.PMID: 27195698 PMID: 32876475 PMID: 24510467
In fact, It is higher in the post feeding samples compared to the samples obtained before feeding.
Older people may have a lower rate of cholesterol synthesis because of a reduced organ function or diseases. PMID: 31930729

Butter is not predictive of coronary heart disease.PMID: 9229205

Physico-chemical characterizations:Build and maintain the integrity of the cell membrane. It acts as a protective barrier by maintaining the fluidity, stability and regulating the passage (permeability) of molecules in and out of cells.PMID: 29874108 PMID: 28417231 PMID: 27150091

Communication:Plays a role in various cellular signaling pathways.
Acting as a specific ligand for proteins such as Smoothened (SMO) in the Hedgehog signaling pathway.PMID: 28700381 PMID: 30906624 PMID: 23847008

It is the precursor for the production of sex hormones like Testosterone, Estrogen, Progesterone and (corticosteroids) adrenal glands, including cortisol and aldosterone

It acts in Insulation of nerve fibers (myelin sheath) and helps transmit nerve signals efficiently.

Precursor of vitamin D and plays an important role in metabolism of vitamin A, D, E & K.

It is a precursor for bile acids, which help fat digestion and absorption.
Bile acids also act as signaling molecules (messenger/Communicator)  that regulate blood glucose, fats, and energy metabolism. They change how gastrointestinal hormones, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), are made and how they work in the liver. The dysregulation (deficiency/imbalance of metabolism) of bile acid metabolism can lead to metabolic disorders.PMID: 33800566

Helps protect cells from oxidative stress by acting as an antioxidant. Hence, it is essential.

Cholesterol is not soluble in blood because blood contains a good amount of water and fats are hydrophobic. Hence, they need a special protein carrier called lipoprotein that is Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) to transport from one place to other within the body; hence, they play an important role.

• Chylomicrons are very large particles type of lipoprotein that mainly carry dietary fats, including cholesterol (fatty acids from your food). They are made in the digestive system by intestinal cells and so are influenced by what you eat.
  Chylomicron particles are the primary carrier of dietary (exogenous) cholesterol, while LDL particles are the primary carrier of endogenous cholesterol.PMID: 31846520 PMID: 29763186. The production and metabolism of chylomicron and LDL particles are different.PMID: 25974693 PMID: 29603652
• Very-low-density lipoprotein (VLDL) particles also carry triglycerides to tissues. But the liver makes them. As the body’s cells extract fatty acids from VLDLs, the particles turn into intermediate density lipoproteins, and, with further extraction, into LDL particles.PMID: 32646941
• Intermediate-density lipoprotein (IDL) particles form as VLDLs give up their fatty acids. Some are removed rapidly by the liver, and some are changed into low-density lipoproteins.
• Low-density lipoprotein (LDL) particles are smaller and even richer in pure cholesterol, since most of the triglycerides they carried are gone. LDL transports cholesterol from the liver to various tissues. PMID: 29603652 LDL is known as “bad” cholesterol because it delivers cholesterol to tissues and is strongly associated with the buildup of artery-clogging plaque.
• High-density lipoprotein (HDL) particles are called “good” cholesterol because some of them remove cholesterol from circulation and from artery walls and return it to the liver for excretion.

Low levels of LDL cholesterol may increase the risk for abnormalities such as cancer, premature birth, psychiatric disorders such as anxiety, depression, and suicide attempts. However, there is no evidence to suggest a direct link.PMID: 31097159
Their size also plays a crucial role, pattern “B” lipoprotein has small dense LDL particles while in pattern “A” the size of LDL particles are large.PMID: 22650003

Small, dense LDL particles are more likely to be oxidized, have a higher permeability in the endothelium of arterial walls, and are usually high in specific lysophospholipids, which suggests that they are more likely to be inflammatory. Therefore, small, dense LDL particles are more atherogenic (heart problems), dyslipidemia (high cholesterol), insulin resistance, type 2 diabetes, and metabolic syndrome than large LDL particles. PMID: 33586462 PMID: 32295829 PMID: 32276631 PMID: 34340681

Increased dietary cholesterol intakes may increase the size of LDL particles, and reduce the numbers of small, dense LDL particles.

A RCT, double-blind, placebo study & meta-analysis of RCT studies showed plant sterols at a dose of approximately 2–3 grams per day, consumed as part of healthy diets, may decrease LDL cholesterol levels by approximately 12-13%.PMID: 29795368 PMID: 24780090

Increased numbers of large HDL particles have been reported after dietary cholesterol intake.PMID: 29699812
Reduction of excess dietary carbohydrates and body weight also improved large HDL levels.PMID: 27847194

What is Apolipoprotein?
Apo-: the Greek word “apo,” which means “away from” or “separate.” The term “apolipoprotein” suggests that these proteins are involved in the separation and movement of fats.
Lipoproteins: The term “lipoproteins” is a combination of “fats” and “protein.”

Types and Functions: 
ApoA: Associated with high-density lipoproteins (HDL). These lipoproteins are often referred to as “good cholesterol” because they help transport cholesterol away from tissues to the liver for elimination.
ApoB: Associated with low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). LDL is typically referred to as “bad cholesterol” because high levels can contribute to the buildup of cholesterol in arteries.
ApoC: Found in various lipoproteins and plays a role in regulating lipoprotein metabolism.
ApoE: Found in several lipoproteins, including VLDL, LDL, and HDL. It’s important for the metabolism of these lipoproteins and is associated with the clearance of cholesterol from the bloodstream.
ApoD, ApoF, ApoH, etc.: Some Other apolipoprotein with varying functions.

Phospholipids are associated with the brain (nerve tissue).
Part of the myelin sheath sphingomyyelin.

Palmitic and Stearic acids may stimulate cholesterol synthesis more than other dietary fatty acids.
Fatty acid-stimulated cholesterol production (biosynthesis) can contribute to increased serum cholesterol concentrations.

Plant sterols (adequate amounts) are well-known to inhibit intestinal cholesterol absorption significantly. Plant sterols have been found to change the expression of genes that control cholesterol transport and metabolism in the liver and small intestine PMID: 34787152 PMID: 30717222 PMID: 28158760. Dietary supplementation with plant sterols has been shown to reduce cholesterol absorption in the small intestine, PMID: 31413246. They are not absorbed from healthy intestinal cells in animals or humans.PMID: 30279620
MECHANISM:
One hypothesis is that plant sterols interact with cholesterol at the level of micelle formation (a small gathering of molecules with tails that stick together in the middle and heads that interact with the surrounding liquid. This phenomenon is actually really important in our bodies and when cooking, as it helps things like fats and oils mix with water-based substances, which allows us to digest and absorb nutrients and make delicious dishes!PMID: 34787152.
They interact with enzymes or transfer proteins at the level of intestinal cells.

Dietary fiber-rich foods such as whole oats, whole barley, legumes, peas, beans, flax seeds, apples, and citrus foods are another dietary agent with established cholesterol-lowering activities.PMID: 27807734

Three major biological mechanisms have been proposed to explain the cholesterol-reducing effects of soluble dietary fibres such as β-glucan from oats, pectin from Fruits and vegetables, guar gum and psyllium.

1. Prevention of bile salt re-absorption from the small intestine, leading to an excess fecal bile salt excretion.
2. Reduced glycemic response, leading to lower insulin stimulation of hepatic cholesterol synthesis.
3. Physiological effects of fermentation products of SDF, mainly propionate.
4. In vitro, bile salt micelles “bind” to SDF, preventing their re-absorption.PMID: 21776465.

Approximately 3 grams of β-glucan from oats, that is, 84 grams of oats/day (dosage depends on individuals), may lower LDL-cholesterol and total cholesterol levels by 7%, and 6%, respectively PMCID: PMC7258283 PMID: 31638148.
The consumption of 1 gram per day of pectin may reduce cholesterol levels by approximately 5 mg/dl.PMID: 22190137

Epidemiological and meta-analysis of prospective cohort studies have consistently reported an inverse association (eating more whole grains and its lowering heart health problems) between consumption of whole grain products and cardiovascular disease PMID: 32782386 PMID: 34277690 PMID: 32224906 PMID: 31146435 PMID: 31361320

Soy:Meta-analysis, Meta-Analysis of RCT studies have suggested a reduction of up to 3-4% to 7% in LDL cholesterol concentrations after consumption of adequate amounts of soy protein.PMID: 31006811
The approximate intake of 25 grams of soy protein may be sufficient to produce significant cholesterol-lowering effects, but there is no defined dose-response study. Further studies are needed to determine the optimal dosage.PMID: 33894258
RCT PMID: 28661316

Garlic:600 mg garlic allicor (Allium sativum) was associated with significant reductions in both total and LDL cholesterol levels by 7-8% and 12-14%, respectively.PMID: 25525386
The clinical trial showed no significant difference for raw or powdered garlic or garlic extract via injection, but not ingestion at a dose of approximately 4 grams per day for up to 6 months.PMID: 30479841

A meta-analysis of RCT, double-blind, placebo-controlled trials has revealed that different garlic preparations may exhibit varying effects. For instance, garlic powder and aged garlic extract have been found to be more effective in reducing serum Total Cholesterol levels, whereas garlic oil has been found to be more effective in lowering serum Total triglyceride levels.PMID: 22234974

Almond:
Systematic review and meta-analysis of RCT showed, consumption of 25–168 grams per day almonds may reduce in both total and LDL cholesterol levels or increase HDL cholesterol levels.PMID: 27752301 PMID: 28615375 PMID: 23251793

walnuts:
Meta-analysis and other studies have shown that consuming walnuts significantly lowers both total and approximately 9-16% LDL cholesterol levels.PMID: 24500935 PMID: 31030167 PMID: 15562184

Flaxseed:
Flaxseed contains several beneficial phytochemicals, including ALA and lignin, which reduces both total and LDL cholesterol, but currently, it is not well-established.PMID: 29779483

Saponins and flavonoids:
Saponins and flavonoids are natural compounds found in plants have been reported to have cholesterol-lowering activities.PMID: 33084093 PMID: 25479247

The Portfolio diet such as nuts, plant sterols, viscous fibers, and soy protein has been associated with significant reductions in LDL cholesterol levels and certain anti-inflammatory markers.PMID: 32615714

From a mechanistic standpoint, this makes sense. In the body, HDL acts to remove cholesterol from specialized cells called macrophages.
In some contexts, HDL can become damaged, transforming into something that actually promotes damage to our blood vessels. 
The idea that raising HDL might be beneficial came from clinical studies, including the coronary Drug Trial (1965-1974), where the effects of niacin were examined.

Pharmaceutical labs are working on targeting a molecule in our body called cholesteryl ester transfer protein, more easily referred to as CETP. Studies have shown that blocking the action of CETP leads to an increase in HDL levels in the blood, and, based on the notion that increased HDL is beneficial, it is thought that these drugs would be a great option.
A CETP inhibitor drug produced by Pfizer was shown to increase HDL levels without significantly affecting LDL levels.
However, a clinical trial showed that when provided in combination with another cholesterol-lowering medication called a statin (we will get to these later), torcetrapib treatment was associated with a 50% increase in deaths from cardiovascular disease compared to the placebo. These results occurred because torcetrapib was reported to increase blood pressure.
Some criticisms regarding torcetrapib surrounded the idea that this was not a “pure” medication, especially considering that the blood pressure effect does not seem to be associated with the mechanism of torcetrapib action.Hence CETP inhibition has not been totally abandoned.

However, do HDL levels really matter if LDL levels are in check? In other words, is there any benefit to raising HDL levels if LDL levels are adequately treated? Conclusions from the AIM-HIGH study suggest that the answer is no. Statins are drugs that inhibit the natural ability of our body to generate cholesterol and result in the reduction of LDL cholesterol in the blood. 

All statins have been reported to be associated with adverse side effects, especially when administered at high doses². These side effects include memory problems, sleeping issues, and, most commonly, that which is associated with muscle. For some, these muscle issues might just be minor. For others, however, statin use may come with more serious muscle problems, and this is catching some attention (see this post by Laura Newman). Based on this, as well as results published in November of 2010 in the Lancet, which reported a significant increase in the number of patients experiencing a muscle condition called myopathy as a result of high-dose statins (80mg per day), the FDA has issued the following safety announcement.

The reported frequency of adverse side effects relating to statin usage is 5% in randomized clinical trials, but can reach up to 20% in the clinic^3,4. It is thought that this discrepancy arises because of patient selection in these randomized clinical trials, which generally tend to exclude groups (such as women or the elderly) who have a higher rate of statin intolerance. Furthermore, patients who are heavy drinkers, those who have a pre-existing condition (such as diabetes), or those taking a cocktail of medications are typically excluded. Yet, these people are prescribed statins in real life.

Statin drugs break down muscle tissue excessively when you work, statin drugs interfere with mevalonate pathway in the liver which produces co enzymes q10 from precursors L-Tyrosine. 

Framingham Heart Study:The Framingham Heart Study began the concept of studying multiple generations to understand heart diseases in 1948 with 5,209 adult men and women, aged between 30 and 62 years, with no history of heart attack or stroke. The primary goal of the study was to identify common factors that contribute to cardiovascular disease. The study originated in the town of Framingham, USA, is a long-term, ongoing cardiovascular cohort study.PMID: 5858592 It is a long-term, ongoing cardiovascular cohort study, publishing over 3,000 peer-reviewed scientific papers. 
PMID: 24084292

1960:

1. Cigarette smoking, obesity, Increased cholesterol and elevated blood pressure are associated with an increased risk of heart disease.  
2. Exercise is associated with a decreased risk of heart disease.

1970:

1. In postmenopausal women, the risk of heart disease is increased, compared with premenopausal women.
2. The interrelation of stress, social isolation and behavior (Psychosocial) factors affect the risk of heart disease.

1980:

1. High levels of HDL cholesterol are associated with a lower risk of heart disease.
2. There is no evidence to show that filtered cigarettes are less likely to get heart disease than cigarettes that don’t filter.

1990:

1. Having an enlarged (hypertrophy) left ventricle of the heart is associated with an increased risk of stroke.
2. Elevated blood pressure can progress to heart failure. 

2000:

1. “High normal blood pressure” called prehypertension in medicine; it is defined as a systolic pressure of 120–139 mm Hg and a diastolic pressure of 80–89 mm Hg) is associated with increased risk of cardiovascular disease. The lifetime risk of developing elevated blood pressure is 90%.
2. Obesity is a risk factor for heart failure.
3. Serum aldosterone levels predict risk of elevated blood pressure.
4. Some genes increase the risk of atrial fibrillation. 
   
   
   

Tazloc:
Tazloc (telmisartan) is an angiotensin (hormone) receptor blocker PMID: 34419631 PMID: 31330445
PMID: 32763272 PMID: 32356926.

Angiotensin is a peptide hormone that causes blood vessels to tighten (vasoconstriction) and an increase in blood pressure. It is part of the renin–angiotensin system, PMID: 31602467.
Angiotensin also causes (stimulate) the release of aldosterone (Hormone) to promote sodium retention by the kidneys PMID: 24206658 PMID: 34714114 PMID: 20720527.
It has a direct effect on the kidneys to increase sodium reabsorption, PMID: 25858030 PMID: 24694992.
In the brain increases the desire for salt, thirst sensation PMID: 28833692 PMID: 27991901 PMID: 21896148 and vasopressin (antidiuretic hormone) secretion PMID: 21123762 PMID: 11166690 PMID: 8876246 PMID: 8638700 PMID: 8876246.
Angiotensin increases fat mass by up regulating adipose tissue Lipogenesis (increases activities of lipogenic enzymes) and down regulating lipolysis.PMID: 16703000 PMID: 15181043 PMID 20944545 Means it helps in gaining fat and making it difficult to lose fat. 

Tazloc works by blocking the action of an angiotensin II by relaxing blood vessels and lowers blood pressure to treat high blood pressure (hypertension) PMID: 10878697 PMID: 14513945 PMID: 4127309.
Tazloc can cause weight gain in some people through increased appetite, decreased metabolism and Fluid retention PMID: 12563538 PMID: 18382675 PMID: 32528286 PMID: 32587520 PMID: 31075789.
The exact mechanism of how it causes weight gain is not fully understood, PMID: 11603882 PMID: 31952459 PMID: 34575210

Cholesterol is an alcohol compound which cannot burn or oxidized like fat, it can only get rid of by the reverse transport of HDL system.

The body tightly controls cholesterol adsorption from food, most cholesterol is excreted, without any genetic problems average person absorbs less than 10% of cholesterol from food.

Cholesterol heated at high temperature gets oxysterols (which may be harmful:Theory)