Cholesterol pools intestinal cells

Cholesterol is formed in the liver (85%) and intestine (12%) - this constitutes 97% of the body s cholesterol synthesis of 3.2 mmol/day (= 1.25 g/day). Serum cholesterol is esterized to an extent of 70-80% with fatty acids (ca. 53% linolic acid, ca 23% oleic acid, ca 12% palmitic acid). The cholesterol pool (distributed in the liver, plasma and erythrocytes) is 5.16 mmol/day (= 2.0 g/day). Homocysteine stimulates the production of cholesterol in the liver cells as well as its subsequent secretion. Cholesterol may be removed from the pool by being channelled into the bile or, as VLDL and HDL particles, into the plasma. The key enzyme in the synthesis of cholesterol is hydroxy-methyl-glutaryl-CoA reductase (HGM-CoA reductase), which has a half-life of only 3 hours. Cholesterol is produced via the intermediate stages of mevalonate, squalene and lanosterol. Cholesterol esters are formed in the plasma by the linking of a lecithin fatty acid to free cholesterol (by means of LCAT) with the simultaneous release of lysolecithin. (s. figs. 3.8, 3.9) (s. tab. 3.8)... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

From these brief considerations, it is apparent that the pool(s) of cholesterol in the intestinal epithehal cell subserve(s) at least two very different functions. On the one hand, the epithehum must have a constant supply of cholesterol for membrane synthesis and differentiation since the mucosal surface is constantly renewing itself. On the other hand, cholesterol also must be available for incorporation into the... 

Thus, in summary, it may be concluded that much of the cholesterol synthesized in the intestine is apparently used for local purposes. Under circumstances where there is no triglyceride absorption taking place essentially no newly synthesized sterol of intestinal origin can be detected in the lymphatic outflow from the gut. During active triglyceride absorption, however, the rate of sterol synthesis increases markedly in the intestinal absorptive cells, and a portion of this newly synthesized cholesterol is incorporated into chylomicrons and other intestinal lipoproteins and delivered into the lymph. Thus, both the rate of sterol synthesis by the intestine and the rate of entry of this sterol into the body pools is partially dictated by the rate of triglyceride absorption. 

On the basis of the data reviewed in this chapter, it seems likely that there are functionally distinct pools of cholesterol in the intestinal epithelial cell that serve different metabolic functions. These pools are illustrated diagrammatically in the model of an epithelial cell shown in Fig. 14. Pool A is defined as having been derived largely from the uptake of luminal unesterified cholesterol (arrow 1) and serves as a major substrate for the CoA-dependent esterification reaction (arrow 2). The cholesterol esters that result from this reaction are incorporated into the hydro-phobic core of the chylomicron particle. Following cholesterol feeding there is a marked increase in apparent ACAT activity in the intestinal epithelium that seems to be related to an increase in the amount of intracellular cholesterol available to the enzyme under the in vitro conditions of the assay rather than to an increase in the... 

Fig. 14. Diagranunatic representation of the pools and fluxes of cholesterol within the intestinal mucosal cell. Based upon the experimental data presented in this review, it is likely that at least 3 distinct subpools of cholesterol exist within the cell these include pool A, which is derived from sterol absorbed from the intestinal lumen (arrow 1) and serves principally as a substrate for acyl-CoA cholesterol acyhransferase (ACAT) (arrow 2) while that in pool B is supplied primarily by de novo synthesis from acetyl-CoA (arrow 4). pool C presumably receives a major contribution of sterol from pool B (arrow S) and a lesser contribution from pool A (arrow 3). The free sterol in this metabolically active pool is used for the synthesis of cell membranes (arrow 6) and for the surface coat of nascent chylomicrons (arrow 7). Triglycerides are also absorbed (arrow 8) and secreted in chylomicrons (arrow 9) into lymph. Finally, low-density lipoproteins (LDL) are taken up from the plasma and contribute to the metabolically active pool of cholesterol (arrow 10) (41J.

Pools A and B also appear to be functionally distinct with respect to the role of the sterol in these pools to effectively regulate the rate of cholesterol synthesis within the intestinal epithehal cell. For example, cholesterol feeding in the rat and in man... 

The relative importance of each of these contributions to pool C is likely to be different in epithelial cells located at different points along the villus-crypt axis. The fact that cholesterol derived from synthesis and from the uptake of LDL is critically important for membrane formation and differentiation is suggested by the finding that 70-80% of total mucosal sterol synthetic activity and LDL transport activity are localized to the immature cells of the lower villus and crypt regions in both the proximal and distal intestine. In the mature absorptive cells of the upper villus in the jejunum, where most sterol absorption takes place, the rate of cholesterol synthesis appears to be suppressed. In the absence of fat absorption, cholesterol newly synthesized in these cells apparently is sloughed into the lumen and not reabsorbed. However, with active triglyceride absorption cholesterol synthesis in these cells is increased and a portion of this sterol appears in the intestinal lymph. Only under this condition does pool B apparently supply sterol for lipoprotein formation. 

The most common drugs used to lower hepatic cholesterol by increasing the formation of bile acids do so by interrupting the enterohepatic circulation. These bile acid sequestrants (e.g., cholestyramine) are Insoluble resins that bind tightly to bile acids in the lumen of the intestines, forming complexes that prevent IBAT-medlated absorption by intestinal epithelial cells. The complexes are excreted in the feces. The resulting decrease in the return of bile acids to the liver causes a drop in the hepatic bile acid pool. As... 

Cholesterol is packaged in chylomicrons in the intestine and in very-low-den-sity lipoprotein (VLDL) in the liver. It is transported in the blood in these lipoprotein particles, which also transport triacylglycerols. the triacylglycerols of the blood lipoproteins are digested by lipoprotein lipase, chylomicrons are converted to chylomicron remnants, and VTDT is converted to intermediate-density lipoprotein (IDL) and subsequently to low-density lipoprotein (LDL). These products return to the liver, where they bind to receptors in cell membranes and are taken up by endocytosis and digested by lysosomal enzymes. LDL is also endocy-tosed by nonhepatic (peripheral) tissues. Cholesterol and other products of lysosomal digestion are released into the cellular pools. The liver uses this recycled cholesterol, and the cholesterol that is synthesized from acetyl CoA, to produce VLDL and to synthesize bile salts. 

Cholesterol within the intestinal lumen consists of a mixture of free and esterified cholesterol of both exogenous (dietary) and endogenous origin, the latter being derived chiefly from sterols reaching the intestinal lumen in bile and other intestinal secretions and from desquamation of mucosal cells. After movement across the cell membrane into the mucosal cell, cholesterol mixes with the intracellular pool which, in part, is also derived from cholesterol synthesized de novo from acetate by the epithelial cell. A major portion of this pool is esterified with long chain fatty acids, incorporated into chylomicrons, and then released into the intestinal lymph. 

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