Intestinal cholesterol pools

Tissues synthesizing most of the body s cholesterol Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues make the largest contribution to the body s cholesterol pool. 

An opposite effect is at the basis of the up-regulation of LDL receptors in response to treatments with bile acid sequestrants, intestinal cholesterol absorption inhibitors, and HMG-CoA reductase inhibitors. The first class of drugs inhibits the intestinal reabsorption of bile acids, thus promoting increased conversion of cholesterol to bile acids in the liver. The increased demand for cholesterol results in activation of the SREBP system and upregulation of LDL receptor synthesis (as well as cholesterol synthesis via upregulation of HMG-CoA reductase). Similarly, inhibition of intestinal cholesterol absorption with ezetimibe results in a reduction in the hepatic cholesterol pool... 

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. 

Ann Jeina was treated with cholestyramine, a resin that binds some of the bile salts in the intestine, causing these resin-bound salts to be carried into the feces rather than recycled to the liver. The liver must now synthesize more bile salts, which lowers the intrahepatic free cholesterol pool. As a result, hepatic LDL receptor synthesis is induced, and more circulating LDL is taken up by the liver. 

The magnitude of these metabolic pathways is different in the various mammalian species. In man, in steady-state conditions, cholesterol turnover is approximately 0-8-1-2 g/day. Total exchangeable cholesterol in man is about 60 g, and one-third may be attributed to a rapid turning-over pool (A) (including liver, plasma, erythrocytes and, possibly, intestine) the remainder to a slower pool (B) including, notably, skeletal muscle, skin and adipose tissue cholesterol Pool A receives dietary cholesterol and supplies most of the cholesterol for degradation and excretion both compartments synthesize the sterol and interexchange it... 

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included in a pooled analysis of two phase-II studies, both lasting for 12 weeks ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1). In 668 patients who took ezetimibe with simvastatin, the adverse effects were similar to those with simvastatin alone (2). 

Colestyramine is an oral anion-exchange resin, which binds bile acids in the intestine. Bile acids are formed from cholesterol in the liver, pass into the gut in the bile and are largely reabsorbed at the terminal ileum. The total bile acid pool is only 3-5 g but, because such enterohepatic recycling takes place 5-10 times a day, on average 20-30 g of bile acid are delivered into the intestine every 24 hours. Bile acids bound to colestyramine are lost in the faeces and the depletion of the bile acid pool stimulates conversion of cholesterol to bile acid the result is a... 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

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. 

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]. 

According to the regulatory model in Fig. 14, the inhibitory effects of bile acids on cholesterol 7a-hydroxylase may be counteracted to some extent by the stimulatory effect of some bile acids on intestinal absorption of cholesterol which may increase the substrate pool for the cholesterol 7a-hydroxylase. The difficulties in different laboratories to get concordant results in studies of the effects of feeding... 

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... 

Each newly synthesized intestinal apo B-containing lipoprotein particle (chylomicron) consists of a core lipid droplet rich in TG, surrounded by a monolayer made up mainly of protein, phospholipids, and cholesterol. The chylomicron lipid core contains a small amount of CE. The lipids of TG-rich particles are in a dynamic equilibrium where each lipid can exchange rapidly between the surface and core. As a result, while the great majority of TG is in the core, the surface contains a small but rapidly replenished pool ofTG which is the direct substrate of the plasma lipases responsible for chylomicron metabolism in the circulation. 

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