Cholesterol

Cholesterol (from the Greek chole=bile and stereos=solid) is a sterol (a combination steroid and alcohol), a lipid found in the cell membranes of all body tissues, and is transported in the blood plasma of all animals. Trace amounts of cholesterol are also found in plant membranes.
Cholesterol has several functions, such as:

• it helps to build and maintain cell membranes: it regulates membrane fluidity over a wider range of temperatures
• some research indicates that cholesterol may act as an antioxidant
• it aids in the manufacture of bile
• it is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D and of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterone, and derivatives).
• it has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane
• It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions

Most of the cholesterol is synthesized by the body and some has dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord, brain, and atheromata (arterial plaques). Cholesterol plays a central role in many biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles which have an exterior composed mainly of water-soluble proteins.

In recent years, the term "bad cholesterol" has been used to refer to cholesterol contained in LDL (low-density lipoprotein) which, according to the lipid hypothesis, is thought to have harmful actions, and "good cholesterol" to refer to cholesterol contained in HDL (high-density lipoprotein), thought to have beneficial actions.

Cholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes.

Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20 – 25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person of about 150 pounds (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg. Of the cholesterol input to the intestines via bile production, 92-97% is reabsorbed in the intestines and recycled via enterohepatic circulation.

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, while 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, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 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 SRE (sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.

Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.

Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.

The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly fats in the form of triglycerides and cholesterol. In the liver, chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to low-density lipoprotein (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol"*.

High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Hypercolesterolemia*

Hypercholesterolemia (literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease. It is closely related to the terms "hyperlipidemia" (elevated levels of lipids) and "hyperlipoproteinemia" (elevated levels of lipoproteins). Familial hypercholesterolemia is a rare genetic disorder that can occur in families, where sufferers cannot properly metabolise cholesterol.

If the hypercholesterolemia is hereditary (familial hypercholesterolemia), there is more often a family history of premature, earlier onset atherosclerosis, as well as familial occurrence of the signs mentioned above.

Yet, there are a number of secondary causes for high cholesterol:

• Diabetes mellitus and metabolic syndrome
• Kidney disease (nephrotic syndrome)
• Hypothyroidism
• Anorexia nervosa
• Zieve's syndrome
• Family history
• Diet: Saturated fat raises blood cholesterol levels. Although dietary cholesterol exerts some influence, the regulatory mechanism of the liver upon absorption of cholesterol decreases the effect of dietary cholesterol on total cholesterol levels. Thus it is mainly by limiting the amount of saturated fat in one's diet that helps lower total serum cholesterol.[citation needed]
• Weight:Being overweight is a definite risk factor for heart disease. It also tends to increase your cholesterol. Losing weight can help lower your LDL and total cholesterol levels, as well as raise your HDL and lower your triglyceride levels.
• Physical Activity:Lack of physical activity is a risk factor for heart disease. Regular physical activity can also help lower LDL (bad) cholesterol and raise HDL (good) cholesterol levels. It also helps you lose weight.

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