By the way, HYPOCHOLESTEROLEMIA is usual in liver disease too (unless the primary problem is obstruction of bile flow -- why?), since the liver isn't producing LDL's.
In addition, endogenous24(S),25-epoxycholesterol is a natural ligand for the liver X receptors whichinduce expression of cholesterol efflux-related genes ().
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.
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.
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.
(This is part of the reason for the silly myth that "too low cholesterol is bad for you".) COAGULOPATHY of liver disease (NEJM 365: 147, 2011)results from diminished hepatic synthesis of factors II, V, VII (first to go), IX, and X.
Presentation Summary : Types of lipoproteins are different in lipid & protein composition & therefore, they differ in: - ... High Density Lipoproteins (HDL) Synthesis: by intestine and liver.
For instance, thisoxysterol repressed the activity of a key rate-controlling enzyme in cholesterolbiosynthesis, hydroxymethylglutaryl (HMG)-CoA reductase.