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Start studying Cholesterol synthesis and metabolism
Bile salts are secreted at a rate of 24 g/day, but synthesized at a rate of only 0.4 g/day in the average individual. This is because, once bile salts have completed their functions in the biliary tree and intestine, almost all are reabsorbed in the distal ileum and returned to the liver through portal venous circulation. Less than 5% of bile salts are lost in the feces each day, which amounts to about 0.4 g/day. The synthesis of bile salts in the liver is adjusted by the body to match the fecal excretion. Considering that cholesterol is the substrate for bile salt synthesis in the liver, a loss of 0.4 g/day of bile salts translates to a loss of the same quantity of cholesterol (i.e., 0.4 g/day).
p. into bile at the rate of up to 2 g/day. The average diet consists of about 0.4 g/day of cholesterol. Therefore, the amount of cholesterol that is derived from bile in the intestine is up to 5-fold in excess of the amount that is taken in through the diet. The biliary cholesterol and dietary cholesterol are admixed in the intestine to form a pool of cholesterol molecules that are indistinguishable. The average individual absorbs 50% of the cholesterol that passes through the intestine each day. This means that 50% is lost in the feces, amounting to 1.2 g/day.
Synthesis of cholesterol
- Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including
ovaries, testes, and placenta, make the largest contributions to the body’s cholesterol pool.
- The pathway is endergonic, being driven by hydrolysis of the high-energy thioester bond of acetyl coenzyme A (CoA) and the terminal
phosphate bond of adenosine triphosphate (ATP).
Synthesis of 3-hydroxy-3-methylglutaryl (HMG) CoA
- The first two reactions in the cholesterol synthetic pathway are similar to those in the pathway that produces ketone bodies .
- They result in the production of HMG CoA .
What occurs in the first steps of cholesterol synthesis
In a study in which transgenic mice with high-level expression of human and both on the apical membrane of enterocytes and on the canalicular membrane of hepatocytes, were generated, transgene over-expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and bile cholesterol levels were increased more than fivefold. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice.. These results demonstrate that increased expression of and selectively drives bile neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol endogenous synthesis.
-binding cassette (ABC) transporters, and are supposed to limit sterol absorption and to promote bile sterol excretion in humans. and are members of the -binding cassette transporter superfamily which contains membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. Genetic variation in these genes in involved in a wide variety of human disorders, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects and drug resistance in tumour cells.
Conservation of the -binding domains of these genes has allowed the identification and classification of new members of the superfamily based on nucleotide and protein sequence homology.
A typical transporter has four domains or subunits, two of which are hydrophobic and are predicted to span the membrane multiple times in an alpha-helical conformation and two of which bind nucleotide (ATP) and are exposed to the cytoplasm
We can distinguish full-size transporters with two trans-membrane domains and two nucleotide-binding domains encoded by a single gene and half-size transporters with one nucleotide-binding domain and one trans-membrane domain, that either form homodimers or heterodimers. The trans-membrane domains provide the transport pathway for a particular substrate, and the nucleotide-binding domains power the transport by hydrolysis.
The nucleotide-binding domains share considerable sequence homology across the entire family and have a similar three-dimensional fold that consists of a core nucleotide-binding subdomain that is common to other ases and an alpha-helical subdomain that is specific to proteins. Conservation of the -binding domains of these genes has allowed the identification and classification of new members of the superfamily based on nucleotide and protein sequence homology.
The Synthesis of Cholesterol. - Cholesterol-And …
Scavenger receptor class B type I (SR-BI) is also a likely element of intestinal cholesterol absorption. SR-BI is a 82 kDa membrane protein mostly expressed in liver and steroidogenic tissues. It binds native high density lipoproteins (HDL), or oxidized and anionic phospholipids and mediates both the selective uptake of cholesteryl ester by the liver and free cholesterol efflux from cells of peripheral tissues. SR-BI is also expressed in enterocyte brush border membranes mainly at the top of intestinal villosities and in the proximal part of intestine where cholesterol absorption mainly occurs. However, the importance of SR-BI in intestinal cholesterol absorption is not so sure since the disruption of SR-BI gene in mice does not affect cholesterol absorption. However, the process seems to be more complex and might depend on the combined actions of transporter proteins involved in uptake and efflux of cholesterol, which could compensate for the lack of SR-BI in the intestine.
p. In a study transgenic mice over-expressing SR-BI primarily in the intestine were generated. The transgene contains the mouse SR-BI gene under the control of the human intestinal specific apolipoprotein (apo) C-III enhancer coupled with the apo A-IV promoter.
This construct induces decreasing SR-BI expression along the gastrocolic axis and an increasing one from the crypt to the top of the villosity.
Thus, SR-BI is expressed where intestinal cholesterol absorption mainly occurs in SR-BI transgenic mice as in wild type littermate.
This study evidences for the first time that SR-BI plays a role in vivo in intestinal cholesterol absorption. Indeed, the intestinal cholesterol uptake determined by radioactive acute phase measurement of plasma cholesterol was doubled at 3 hours after gavage in the transgenic mice. In addition a net increase of tocopherol, a specific marker for chylomicron synthesis, was measured in the plasma of the transgenic mice following gavage with tocopherol.
Interestingly, in contrast to the increased intestinal cholesterol uptake, they observed an unexpected decrease of plasma cholesterol content in all lipoprotein fractions (around 50%), which resembles to the major phenotype observed in animals over-expressing SR-BI in the liver.
A possible explanation is that the rise of intestinal cholesterol absorption is likely balanced by the moderate over expression of SR-BI in the liver inducing an increase of cholesterol catabolism shown by the bile cholesterol secretion enhancement as well as an increase of chylomicrons catabolism.
Liver SR-BI overexpression causes a decrease in plasma apo AI levels increasing clearance in liver, but in this transgenic model, a diminution in plasma apo AI was not observed, whereas cholesterol was decreased by two fold. Apo A-I can be synthesized by the liver through formation or by the intestine associated with chylomicron secretion. Maybe, the intestine could participate in the regulation of apo AI synthesis through an increase of chylomicron secretion, which do not modify cholesterol plasmatic levels, containing mostly triglycerides.
It causes shortening of the carbon chain from 30 to 27 carbons, removal of the two methyl groups at carbon 4, migration of the double bond from carbon 8 to carbon 5, and reduction of the double bond between carbon 24 and carbon 25.
~ Synthesis requires enzymes in both the cytosol and the membrane of the smooth endoplasmic reticulum (ER).
~ The pathway is responsive to changes in cholesterol concentration, and regulatory mechanisms exist to balance
the rate of cholesterol synthesis within the body against the rate of
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Biosynthesis of Fatty Acid and Cholesterol (With Diagram)
A third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound.
Synthesis of Mevalonate
~ The next step, the reduction of HMG CoA to mevalonate, is catalyzed by HMG CoA reductase.
~ It is the rate-limiting and key regulated step in cholesterol synthesis.
in the synthesis of cholesterol are:
Synthesis of Cholesterol
~ Cholesterol is a very hydrophobic compound.
~ It consists of four fused hydrocarbon rings (A-D) called the “steroid nucleus”)
~ It has an eight-carbon, branched hydrocarbon chain attached to carbon 17 of the D ring.
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