Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase
pathway in many cells/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 1,200 to 1,300 mg input
to the intestines (via bile production and food intake), about 50% is typically
reabsorbed into the bloodstream.
Properties
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" which are water soluble and carry
cholesterol and fats internally. The proteins 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 triglyceride fats and
cholesterol (both from food and especially internal cholesterol secreted by the liver
into the bile). In the liver, chylomicron particles give up triglycerides and some
cholesterol and are converted into low-density lipoprotein (LDL) particles which
carry triglycerides and cholesterol on to other body cells. In healthy individuals
the LDL particles are large and relatively few in number. Conversely, large numbers
of small LDL particles are strongly associated with promoting atheromatous disease
within the arteries. (Lack of information on LDL particle number and size is one of
the major problems of conventional lipid tests.)
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. Conversely,
having small amounts of large HDL particles is strongly associated with atheromatous
disease progression within the arteries. (Note that the concentration of total HDL
does not indicate the actual number of functional large HDL particles, another of the
major problems of conventional lipid tests.)
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The cholesterol molecules present in LDL cholesterol and HDL cholesterol are
identical. The difference between the two cholesterol derives from the carrier
protein molecules; the lipoprotein) component.
Regulation
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present,
though the homeostatic mechanisms involved are only partly understood. A higher
intake in food leads to a net decrease in endogenous production and vice versa. 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 Insig-1. 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
"Sterol Regulatory Element" of a number of genes to stimulate their transcription.
Amongst the genes transcribed are the LDL receptor and HMG-CoA reductase. The former
scavenges circulating LDL from the bloodstream, while HMG-CoA reductase leads to an
increase of endogenous production of cholesterol.
A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L.
Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for
their work in 1985.
The average amount of blood cholesterol varies with age, typically rising gradually
until one is about 60 years old. A study by Ockrene et al. showed that there are
seasonal variations in cholesterol levels in humans, more on average in winter.
Function
Cholesterol is an important component of the membranes of cells, providing stability;
it makes the membrane's fluidity stable over a bigger temperature interval. The
hydroxyl group on cholesterol interacts with the phosphate head of the membrane and
the bulky steroid and the hydrocarbon chain is embedded in the membrane. It is the
major precursor for the synthesis of vitamin D, of the
various steroid hormones, including cortisol, cortisone, and aldosterone in the
adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone. The
presence of cholesterol has a direct effect on the fluidity of the membrane. Further
recent research shows that cholesterol has an important role for the brain synapses
as well as in the immune system, including protecting against cancer.
Excretion
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 lecitin and
bilirubin gallstones also occur less frequently.
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