Cholesterol esters metabolism

The purification and properties of LCAT, together with a discussion of its mechanism of reaction are given by Marcel (1982). A number of disease states involve LCAT activity. Familial LCAT deficiency has been described (Glomset and Norum, 1973) and patients with this rare complaint have been thoroughly investigated. Many of the abnormalities seem in such patients have been found in those with cholestasis also. A discussion of cholesterol ester metabolism in relation to other liver diseases and dyslipoproteinaemia has been reported (Marcel, 1982). Similarly, the metabolism of cholesterol esters in relation to arteries and arterial disease has been fully discussed (Kritchevsky and Kothari, 1978). Mammalian steroid sulphates have been reviewed by Farooqui (1981). 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Kaneko, H., M. Matsuo, and J. Miyamoto. 1986. Differential metabolism of fenvalerate and granuloma formation. I. Identification of a cholesterol ester derived from a specific chiral isomer of fenvalerate. Toxicol. Appl. Pharmacol. 83 148-156. 

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

Chylomicrons and VLDL are primarily triglyceride particles, although they each have small quantities of cholesterol esters. Chylomicrons transport dietary trig lyceride to adipose tissue and muscle, whereas VLDL transport triglyceride synthesized in the liver to these same tissues. Both chylomicrons and VLDL have apoC-II, apoE, and apoB (apoB-48 on chylomicrons and apoB-IOO on VLDL). The metabolism of these particles is shown in Figure H5-5. 

Lipoproteins are an important class of serum proteins in which a spherical hydrophobic core of triglycerides or cholesterol esters is surrounded by an amphipathic monolayer of phospholipids, cholesterol and apolipoproteins (fatbinding proteins). Lipoproteins transport lipid in the circulation and vary in size and density, depending on their proteindipid ratio (Figure 7.3). Lipoprotein metabolism is adversely affected by obesity low-density lipoprotein (LDL)-cholesterol and plasma triglyceride are increased, together with decreased high-density lipoprotein (HDL)-cholesterol concentrations. 

Beauveriolides I (19) and III (20), two fungal (Beauveria Spp) metabolites, have been found to be specific inhibitors of lipid droplet formation in mouse macrophages. It has been recently observed that the metabolisms of A[3 proteins and cholesterol esters are closely linked. One of the... 

Cholesterol can be derived from two sources—food or endogenous synthesis from ace-tyl-CoA. A substantial percentage of endogenous cholesterol synthesis takes place in the liver. Some cholesterol is required for the synthesis of bile acids (see p. 314). In addition, it serves as a building block for cell membranes (see p. 216), or can be esterified with fatty acids and stored in lipid droplets. The rest is released together into the blood in the form of lipoprotein complexes (VLDLs) and supplies other tissues. The liver also contributes to the cholesterol metabolism by taking up from the blood and breaking down lipoproteins that contain cholesterol and cholesterol esters (HDLs, IDLs, LDLs see p.278). 

The primary developmental mechanism of the atherosclerotic process is not completely understood. It seems likely that the development of atherosclerosis is preceded by metabolic abnormalities of the synthesis, transport, and utilization of lipids. Lipids such as triglycerides and cholesterol esters are circulated in the blood in the form of particles (lipoproteins) wrapped in hydrophilic membranes that are synthesized from phospholipids and free cholesterol. Cholesterol is transported by particles of various sizes synthesized from triglycerides, cholesterol esters, and phospholipids, each of which plays a very specific role. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

The lipidome profile of mice liver homogenates of free cholesterol, low cholesterol, and high cholesterol diets showed the influence between dietary cholesterol intake and atherosclerosis (17). To get individual metabolite fingerprints, they measured near 300 metabolites such as di- and triglycerides, phosphatidylcholines, LPCs, and cholesterol esters in plasma samples by LC-MS/MS. It was observed that when dietary cholesterol intake was increased, the liver compensated for elevations in plasma cholesterol by adjusting metabolic and transport processes related to lipid metabolism, which... 

It is, of course, also possible that the esterified cholesterol formed in HDL may be removed from plasma by some process other than uptake of the whole HDL particle or LTP-I-mediated transfer to other lipoprotein particles, but this possibility has not been fully investigated. Some evidence that there may be other pathways than these for the removal from plasma of HDL esterified cholesterol comes from the studies of Class et al. (G5, G6), who showed that cholesteryl ether incorporated in rat HDL as a tracer for cholesteryl ester was taken up in vivo by the rat liver (and by other organs) fester than apoA-I tracer (see Section 4.1.2). These studies are complicated by the relatively high concentration of apoE in rat HDL (compared, for instance, to man) and the unknown effect of apoE on HDL cholesteryl ester metabolism in the rat. Further studies on the removal of esterified cholester-... 

When the lipid content of the tonsils from E. L. was compared to a nonsymptomatic control, the main difference was a 50-fold increase in cholesterol esters. This finding prompted the investigators to focus their research on cholesterol metabolism in the probands. As all results of tests... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

In liver cirrhosis, there are several changes reduction in LCAT (with cholesterol ester fall ), HDL and LDL as well as in VLDL, with a corresponding change in their distribution pattern occurrence of hypertriglycerid-aemia and atypical lipoproteins reduction in phospholipid synthesis (28), possibly with greatly impaired structure and function of the biomembranes. Hepatic extraction of bile acids is reduced with the result that they reach the peripheral circulation - even in the early stages of cirrhosis - and give rise to increased serum values. Bile acids have cholestatic and cytotoxic effects. When bile acid metabolism is markedly compromised, enteral absorption of fat-soluble vitamins is impeded, so that A, D, E and K hypovitaminoses may be observed. 

Figure 6-10. Metabolism of chylomicrons and VLDL. LPL = lipoprotein lipase TG = triacylglycerol CE = cholesterol esters circled TG - triacylglycerol of chylomicrons and VLDL 0= inhibits = stimulates.

Figure 26-18 Exogenous lipoprotein metabolism pathway. TG, Triglyceride CE, cholesterol ester FC, free cholesterol Ft, phospholipids HDL, hIgh-density lipoproteins FA, fatty acid LPL, lipoprotein lipase 6, apolipoprotein B-48 A, apolipoprotein A-i C, apolipoprotein C-ll , apolipoprotein E. (From Rifai N. Lipoproteins and apolipoproteins Composition, metabolism, and association with coronary heart disease. Arch Pathol Lab Med 1986 10 694-701. Copyright 1986, American Medical Association.)...

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