Cholesterol is required to build and maintain membranes; it modulates membrane fluidity over the range of physiological temperatures.
The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids.
Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.
The structure of the tetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.
In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes, hydrogen ions, and sodium ions.
Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction.
Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis.
The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane.
Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane.
Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messenger molecules.
In many neurons, a myelin sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.
Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in the gallbladder.
Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, A, D, E, and K.
Cholesterol is an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.
Dietary Sources
Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat contain cholesterol to varying extents.
Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, fish, and shrimp. Human breast milk also contains significant quantities of cholesterol.
From a dietary perspective, cholesterol is not found in significant amounts in plant sources.
In addition, plant products such as flax seeds and peanuts contain cholesterol-like compounds called phytosterols, which are believed to compete with cholesterol for absorption in the intestines.
Phytosterols can be supplemented through the use of phytosterol-containing functional foods or nutraceuticals that are widely recognized as having a proven LDL cholesterol-lowering efficacy.
Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.
However, the benefits of a diet supplemented with phytosterol has been questioned.
Fat intake also plays a role in blood-cholesterol levels. Isocalorically replacing dietary carbohydrates with monounsaturated and polyunsaturated fats has been shown to lower serum LDL and total cholesterol levels and increase serum HDL levels, while replacing carbohydrates with saturated fat was shown to increase HDL, LDL, and total cholesterol levels.
Trans fats have been shown to reduce levels of HDL while increasing levels of LDL. Based on such evidence and evidence implicating low HDL and high LDL levels in cardiovascular disease, many health authorities advocate reducing LDL cholesterol through changes in diet in addition to other lifestyle modifications.
The USDA, for example, recommends that those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily energy needs from saturated fat and fewer than 200 mg of cholesterol per day.
An alternative view is that any reduction to dietary cholesterol intake could be counteracted by the organs compensating to try to keep blood cholesterol levels constant.
Other research has found that an increase in the consumption of saturated fats and cholesterol decreases overall serum cholesterol.
A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect.
The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).
In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP cleavage activating protein) and Insig1.
When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, which allows the complex to migrate to the Golgi apparatus.
Here SREBP is cleaved by S1P and S2P (site-1 and -2 protease), two enzymes that are activated by SCAP when cholesterol levels are low.
The cleaved SREBP then migrates to the nucleus, and acts as a transcription factor to bind to the sterol regulatory element (SRE), which stimulates the transcription of many genes.
Among these are the low-density lipoprotein (LDL) receptor and HMG-CoA reductase.
The LDL receptor former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.
A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their work.
Their subsequent work shows how the SREBP pathway regulates expression of many genes that control lipid formation and metabolism and body fuel allocation.
Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain.
The membrane domain senses signals for its degradation.
Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteosome.
This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein kinase.
Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.
A separate set of American Heart Association guidelines issued in 2013 indicates that patients taking statin medications should have their cholesterol tested 4–12 weeks after their first dose and then every 3–12 months thereafter.
A blood sample after 12-hour fasting is taken by a doctor, or a home cholesterol-monitoring device is used to determine a lipoprotein profile.
This measures total cholesterol, LDL (bad) cholesterol, HDL (good) cholesterol, and triglycerides.
It is recommended to test cholesterol at least every five years if a person has total cholesterol of 5.2 mmol/L or more (200+ mg/dL), or if a man over age 45 or a woman over age 50 has HDL (good) cholesterol less than 1 mmol/L (40 mg/dL), or there are other risk factors for heart disease and stroke.
Other risk factors for heart disease include Diabetes, Hypertension (or use of anti-hypertensive medications), low HDL, family history of CAD and hypercholesterolemia, and cigarette smoking.
The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids.
Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.
The structure of the tetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.
In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes, hydrogen ions, and sodium ions.
Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction.
Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis.
The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane.
Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane.
Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messenger molecules.
In many neurons, a myelin sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.
Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in the gallbladder.
Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, A, D, E, and K.
Cholesterol is an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.
Dietary Sources
Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat contain cholesterol to varying extents.
Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, fish, and shrimp. Human breast milk also contains significant quantities of cholesterol.
From a dietary perspective, cholesterol is not found in significant amounts in plant sources.
In addition, plant products such as flax seeds and peanuts contain cholesterol-like compounds called phytosterols, which are believed to compete with cholesterol for absorption in the intestines.
Phytosterols can be supplemented through the use of phytosterol-containing functional foods or nutraceuticals that are widely recognized as having a proven LDL cholesterol-lowering efficacy.
Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.
However, the benefits of a diet supplemented with phytosterol has been questioned.
Fat intake also plays a role in blood-cholesterol levels. Isocalorically replacing dietary carbohydrates with monounsaturated and polyunsaturated fats has been shown to lower serum LDL and total cholesterol levels and increase serum HDL levels, while replacing carbohydrates with saturated fat was shown to increase HDL, LDL, and total cholesterol levels.
Trans fats have been shown to reduce levels of HDL while increasing levels of LDL. Based on such evidence and evidence implicating low HDL and high LDL levels in cardiovascular disease, many health authorities advocate reducing LDL cholesterol through changes in diet in addition to other lifestyle modifications.
The USDA, for example, recommends that those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily energy needs from saturated fat and fewer than 200 mg of cholesterol per day.
An alternative view is that any reduction to dietary cholesterol intake could be counteracted by the organs compensating to try to keep blood cholesterol levels constant.
Other research has found that an increase in the consumption of saturated fats and cholesterol decreases overall serum cholesterol.
Regulation of cholesterol synthesis
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood.A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect.
The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).
In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP cleavage activating protein) and Insig1.
When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, which allows the complex to migrate to the Golgi apparatus.
Here SREBP is cleaved by S1P and S2P (site-1 and -2 protease), two enzymes that are activated by SCAP when cholesterol levels are low.
The cleaved SREBP then migrates to the nucleus, and acts as a transcription factor to bind to the sterol regulatory element (SRE), which stimulates the transcription of many genes.
Among these are the low-density lipoprotein (LDL) receptor and HMG-CoA reductase.
The LDL receptor former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.
A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their work.
Their subsequent work shows how the SREBP pathway regulates expression of many genes that control lipid formation and metabolism and body fuel allocation.
Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain.
The membrane domain senses signals for its degradation.
Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteosome.
This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein kinase.
Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.
Cholesterol testing
The American Heart Association recommends testing cholesterol every five years for people aged 20 years or older.A separate set of American Heart Association guidelines issued in 2013 indicates that patients taking statin medications should have their cholesterol tested 4–12 weeks after their first dose and then every 3–12 months thereafter.
A blood sample after 12-hour fasting is taken by a doctor, or a home cholesterol-monitoring device is used to determine a lipoprotein profile.
This measures total cholesterol, LDL (bad) cholesterol, HDL (good) cholesterol, and triglycerides.
It is recommended to test cholesterol at least every five years if a person has total cholesterol of 5.2 mmol/L or more (200+ mg/dL), or if a man over age 45 or a woman over age 50 has HDL (good) cholesterol less than 1 mmol/L (40 mg/dL), or there are other risk factors for heart disease and stroke.
Other risk factors for heart disease include Diabetes, Hypertension (or use of anti-hypertensive medications), low HDL, family history of CAD and hypercholesterolemia, and cigarette smoking.
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