Cholesterol inhibition

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

Tocotrienols present in rice bran inhibit the liver microsomal enzyme HMGCoA reductase (Qureshi and Qureshi, 1992), the key enzyme involved in the endogenous synthesis of cholesterol, and this helps to lower the circulating cholesterol. Inhibition of another enzyme, ACAT (Acyl coenzyme A acyl transferase), by y-oryzanol results in lowered LDL-C synthesis and enrichment... 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Which of the following drugs recommended for the lowering of blood cholesterol inhibits the synthesis of cholesterol by blocking 3-hydroxy-3-me thy 1 glutary 1-coenzyme A (HMG-CoA) reductase ... 

Fuhrman, B., M. Rosenblat, T. Hayek, R. Coleman, and M. Aviram. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipo-protein E-deficient mice. J Nutr 2000 130(5) 1124-1131. 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Saturated fatty acids 19 g/1 Increase HDL, small dense LDL, and total cholesterol. Inhibition of bacteria, virus... 

Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., and Tabas, I., 2004, Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages../. Biol. Chem. 279, 37030—37039 Lin, P., Yao, Y., Hofmeister, R., Tsien, R.Y., and Farquhar, M.G., 1999, Overexpression of CALNUC (nucleobindin) increases agonist and thapsigargin releasable Ca2+ storage in the Golgi. J. Cell Biol. 145, 279-289... 

The free cholesterol inhibits the synthesis and/or causes the degradation of HMG-CoA reductase and of LDL receptor. This last step ensures that more cholesterol will not be taken up or made than is needed. 

El-Sohemy, A., Kendall, C.W.C., Rao, A.V., Archer, M.C., Bruce, W.R. 1996a. Dietary cholesterol inhibits the development of aberrant crypt foci in the colon. Nutr. Cancer. 25, 111-117. 

A feedback mechanism operates in which intracellular free cholesterol inhibits HMG-CoA reductase. When the diet is rich in cholesterol, intracellular cholesterol increases in the liver and the biosynthesis of cholesterol is suppressed. Conversely, a low-cholesterol diet, but one with adequate triglyceride, stimulates cholesterol biosynthesis. 

H-10) HMG CoA reductase. This is an important rate-limiting step in cholesterol synthesis. Drugs that act at this step to inhibit HMG CoA reductase can lower blood chole.sterol. Normally, excess cholesterol inhibits HMG CoA reductase by negative feedback on its activity and synthesis, providing a natural control mechanism for cholesterol synthesis. Hereditary differences result in differences in feedback effects. In certain people there is a marked increase in serum cholesterol on increasing cholesterol intake, whereas in others, there is little increase, as the feedback mechanism is functioning more actively. 

Statins, used predominantly in the treatment of hypercholesterolemia, act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which regulates the synthesis of cholesterol. Statins are also agonists of peroxisome proliferator activated receptors (PPARs), which are part of the nuclear receptor superfamily and when activated, can suppress transcription of pro-inflammatory genes (Chinetti et al., 2000). In vitro and in vivo studies have shown that a decrease in serum cholesterol inhibits the production of beta amyloid and plaque (Simons et al., 1998 Fassbender et al.,... 

Various experiments on animals and humans had shown that cholesterol could either be absorbed from the diet, or if the diet was lacking sufficient cholesterol to meet the body s needs, then it could be synthesized. Cholesterol production within the body is controlled by a feedback mechanism in which cholesterol inhibited the enzyme HMG CoA reductase, an enzyme discovered in 1959 by Feodor Lynen et al. (Figure 1.36) at the Max Planck Institute (Munich).24 ... 

Free cholesterol can affect cholesterol metabolism in the body by inhibiting cholesterol biosynthesis. The step at which free cholesterol inhibits its biosynthesis is by inhibiting which of the following processes ... 

A dissociation between HMG-CoA reductase and the cholesterol 7a-hydroxylase has been reported in connection with feeding of cholesterol, tomatidine, sitosterol as well as in scurvy. Feeding cholesterol inhibits HMG-CoA reductase and in most [99,222,238,239] but not all [50] studies a stimulatory effect has been found on cholesterol 7a-hydroxylase. The stimulatory effect may be due to an expansion of the pool of cholesterol available for cholesterol 7a-hydroxylase. Feeding with tomatidine and sitosterol interferes with absorption of cholesterol from the intestine, and the increased HMG-CoA reductase activity is probably due to decreased inhibition by lymph cholesterol [240,241]. The cholesterol 7a-hydroxylase activity is only slightly increased or unaffected under these conditions [240,241]. 

The regulatory function of this enzyme at such an early phase in the cholesterol synthesis, and the findings that a defect in this regulation exists in FH patients, rekindled interest in this enzyme as a target for cholesterol inhibition after years of hands off because of the triparanol experience. 

It is now known that many of the mushrooms presently under cultivation rank above all vegetable and legumes (except soybeans) in protein content, and have significant levels of B and C vitamins and are low in fat. Research has shown that certain cultivated mushrooms reduce serum cholesterol, inhibit tumors, stimulate interferon production and possess antiviral properties. It is no surprise, therefore, that as food plants were developed into cultivars, mushrooms were among those selected. 

FIGURE 8.27 The mode of action of the LDL receptor. A portion of the membrane with LDL receptor and bound LDL is taken into the cell as a vesicle. The receptor protein releases LDL and is returned to the cell surface when the vesicle fuses to the membrane. LDL releases cholesterol in the cell. An oversupply of cholesterol inhibits synthesis of the LDL receptor protein. An insufficient number of receptors leads to elevated levels of LDL and cholesterol in the bloodstream. This situation increases the risk of heart attack. 

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