Lipid metabolism cholesterol biosynthesis

LSSA t Lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) Lipid metabolism/cholesterol biosynthesis... 

Figure 19.12 Regulation of liver acetyl-CoA carboxylase and cholesterol biosynthesis by phosphorylation. ACC indicates acetyl-CoA carboxylase. Bold arrow indicates activation of kinase kinase by fatty acyl-CoA. (Reproduced by permission from Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multi-substrate regulator of lipid metabolism. Trends Biochem Sci 14 20-23, 1989.)...

There are conflicting data on whether the availability of cholesterol and/or cholesteryl esters directly influences apo B secretion. Several studies have suggested that cholesterol supply can regulate VLDL secretion. For example, VLDL production in animals and man is decreased by statin treatment, and inhibition of cholesterol synthesis by a statin, an inhibitor of the rate-limiting step of cholesterol biosynthesis (Chapter 14), reduced VLDL secretion in perfused rat livers (M. Heimberg, 1990) and primary hepatocytes. However, this effect of statins can perhaps be ascribed to increased expression of LDL receptors rather than to a reduction in cholesterol synthesis (Section 7.1). Depletion of cholesterol in rodent hepatocytes by the ABCAl-dependent lipidation of apo A1 (Chapter 19) also decreases VLDL secretion (R. Lehner, 2004). Furthermore, the secretion of apo BlOO-containing VLDLs is increased in primary hepatocytes derived from Niemann-Pick Cl-deficient mice. Niemann-Pick Cl-deficiency causes a severe defect in trafficking of unesterified cholesterol out of the lysosomal/endosomal pathway and consequently, Niemann-Pick Cl-deficient hepatocytes accumulate 5- to 10-fold more unesterified cholesterol than do wild-type hepatocytes. In hepatocytes from Niemann-Pick Cl-deficient mice, cholesterol synthesis is increased and the rate of cholesterol esterification and the amount of the transcriptionally active form of SREBP-1 are also increased (J.E. Vance, 2007). However, because of multiple alterations in lipid metabolism in these hepatocytes, increased VLDL secretion cannot be attributed specifically to increased synthesis of cholesterol or cholesteryl esters. 

See also Cholesterol Biosynthesis, Steroid Metabolism, Steroid Hormone Synthesis, Bile Acids, Lipid-Soluble Vitamins, Plant Hormones... 

A. Mechanism and Effects Fibric acid derivatives (eg, gemfibrozil, fenofibrate, clofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. Tbis interaction with PPAR-a results in increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (Figure 35-2). Cholesterol biosynthesis in the liver is seeondarily reduced. The fibrates reduce serum triglyceride concentrations (Table 35-3). There may be a small reduction in LDL cholesterol and a small increase in HDL levels. 

Much of the endogenous lipid that is eventually used by peripheral tissues is transported in the form of water-soluble ketone bodies, the two most important being jS-hydroxybutyrate and acetoacetate. The metabolic pathway of ketone body formation and its relationship to cholesterol biosynthesis is shown in Fig. 4.10. Four enzymes are Involved in the formation of ketone bodies, namely acetyl-CoA transferase (also known as thiolase), hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), hydroxymethyl-glutaryl-CoA lyase (HMG-CoA lyase) and jS-hy-droxybutyrate dehydrogenase. Tbe last of these catalyses the interconversion of the two principal ketone bodies. All four enzymes are present in liver, the principal site of ketone body formation. Acyl-CoAs are unable to pass through the plasmalemma, and HMG-CoA lyase thus controls the release of ketone... 

Histochemical, cytochemical, developmental, and biochemical studies indicate that much of the brain cholesterol is localized in the lipid-protein layers of the myelin sheath. As a result, this cholesterol is largely removed from the normal metabolic environment of the brain. Thus, although nervous tissue contains relatively large amounts of lipid, biosynthesis and the mean turnover rate of the typical myelin lipids including cholesterol are quite slow. Nevertheless dynamic metabolism may be found in small pools of, for example, cell or organelle membrane, cytoplasmic lipid, or outer parts of the myelin sheath. Such possibilities may serve to explain some of the various anomalous results reported by many workers studying brain cholesterol metabolism. 

NR0B2 t Nuclear receptor subfamily 0, group B, member 2 Lipid metabolism/regulation of cholesterol biosynthesis... 

Thyroid hormones have long been known to affect lipid metabolism. Thyroxine undoubtedly controls cholesterol metabolism serum cholesterol levels are markedly increased in hypothyroidism and decreased in hyperthyroidism. There are various ways by which thyroxine could cause cholesterol to accumulate in blood direct stimulation of the pathway involved in cholesterol biosynthesis block of cholesterol use for further biosynthesis indirect stimulation of cholesterol synthesis by acceleration of pathways that provide precursors of coenzymes needed for cholesterol synthesis and indirect stimulation of cholesterol synthesis by blocking pathways that use those precursors involved in cholesterol synthesis. The exact mechanism by which thyroxine induces the accumulation of cholesterol in serum needs to be elucidated. The effect of thyroid hormones on blood cholesterol must be understood because hypothyroidism is known to enhance the development of experimental arteriosclerosis in animals. 

Several lines of evidence point to a connection between lipid metabolism and scaly skin. Inhibitors of cholesterol biosynthesis such as triparanol and nicotinic acid can produce scaly lesions superficially resembling ichthyosis. A disturbance of cutaneous sterol ester biosynthesis accompanies the hyperkeratosis of essential fatty acid deficiency, and increased ratios of free sterol to sterol esters have been reported in psoriasis and atopic eczema . We have recently shown that epidermal lipid biosynthesis is increased in lesions of psoriasis and lichen simplex, with the free sterol fraction affected more than other lipid classes. 

Cholesterol is present in all animal tissues, and particularly in neural tissue. It is a major constituent of cellular membranes, in which it regulates fluidity (see p. 216). The storage and transport forms of cholesterol are its esters with fatty acids. In lipoproteins, cholesterol and its fatty acid esters are associated with other lipids (see p.278). Cholesterol is a constituent of the bile and is therefore found in many gallstones. Its biosynthesis, metabolism, and transport are discussed elsewhere (see pp. 172, 312). 

Biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the 800 mg/day of cholesterol that the average adult uses up in metabolic processes. By comparison, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day. Much more that 400 mg of bile salts is required and secreted into the intestine per day, and this is achieved by recycling them. Most of the bile salts secreted into the upper region of the small intestine are absorbed along with the dietary lipids that they emulsified at the lower end of the small intestine. They are... 

Structure and Functions of Biological Membranes 381 Metabolism of Fatty Acids 411 Biosynthesis of Membrane Lipids 436 Metabolism of Cholesterol 459... 

Outline of pathways for the biosynthesis of major cellular lipids (other than cholesterol) in a mammalian cell. Most of the metabolism of these lipids occurs on membrane surfaces because of the insoluble nature of the substrates and products. These lipids play three major roles (l) they act as a storehouse of chemical energy, as with triacylglycerols (2) they are structural components of membranes (boxed compounds) and (3) they act as regulatory compounds (underlined), either as eicosanoids, which act as local hormones, or as phosphorylated inositols and diacylglycerols, which function as second messengers. 

Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway (Fig. 1). In contrast to desmosterol and other late-stage lipid-soluble intermediates, HMG is water-soluble, and there are alternative metabolic pathways for its breakdown when HMG-CoA reductase is inhibited so that there is no buildup of potentially toxic precursors. Therefore, of the more than 30 enzymes involved in the biosynthesis of cholesterol, HMG-CoA reductase was a natural target. Substances that have a powerful inhibitory effect on this enzyme, including ML236B (compactin), were first discovered by Endo in a fermentation broth of Penicillium citrinum in the... 

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