Synthesis cholesterol

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

Reduction in semm Hpids can contribute significantly to prevention of atherosclerosis. In 1985 a consensus report indicating that for every 1% reduction in semm cholesterol there is a 2% reduction in adverse effects of coronary heart disease was issued (145). Recommended semm cholesterol concentration was 200 mg/dL for individuals under 30 years of age, and individuals having concentration 240 mg/dL and LDL-cholesterol over 160 mg/dL should undertake dietary modification and possibly pharmacotherapy (146). Whereas the initial step in reducing semm cholesterol is through reduction of dietary cholesterol intake, a number of dmgs are available that can affect semm Hpid profile (see Fat substitutes). The pathway to cholesterol synthesis is shown in Figure 2. 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Mechanism of action of statins cholesterol synthesis pathway... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed cannot be reactivated directly except in the cytosol, where it is used in a much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver. 

A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol. 

Figure 26-4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Asterisk See Figure 18-6.

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-... 

HEGSTED M, KousiK. c s (1994) Rice bran and rice bran oil may lower heart disease risk by decreasing cholesterol synthesis in the body. Lousiana Agriculture, 31 (2) 16-17. 

Fuhrman, B. et al., Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages, Biochem. Biophys. Res. Commun., 233, 658, 1997. 

Hu, X.M. et al.. Inhibition of growth and cholesterol synthesis in breast cancer cells by oxidation products of beta-carotene, J. Nutr. Biochem., 9, 567, 1998. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

Nutritional understanding of the effect of fats in the diet has made considerable progress.26-30 It was understood that saturated fats (see Chapter 3, Section 3.8) were the least beneficial as they raised serum cholesterol. High serum cholesterol is now associated with heart attacks and strokes. There was for this reason pressure over the cholesterol content of foods. This pressure has now been relieved since it appears that dietary cholesterol is not a particularly serious issue. The human body makes cholesterol, so dietary cholesterol does not necessarily affect serum cholesterol level as dietary intake can be compensated for by reduced cholesterol synthesis. 

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