Sterols intestinal absorption

Heinemann T, Axtmann G and Von Bergmann. K 1993. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest 23(12) 827—831. 

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

Plant sterols Commercially available margarines containing hydrogenated plant sterols and sterol esters (predominantly sitostanol esters), when used in place of regular margarine, can reduce LDL plasma cholesterol concentrations. The mechanism by which these compounds lower LDL cholesterol concentrations is to inhibit intestinal absorption of dietary cholesterol and cholesterol secreted into the bile. 

Plant sterols inhibit the intestinal absorption of cholesterol and so have a useful hypocholesterolemic action. They also inhibit endogenous synthesis of cholesterol, by inhibiting and repressing the regulatory enzyme of cholesterol synthesis, hydroxymethylglutaryl (HMG)-CoA reductase. Other compounds synthesized from mevalonate also inhibit and repress HMG-CoA reductase and have a hypocholesterolemic action, including squalene (found in relatively large amounts in olive oil), ubiquinone (Section 14.6), and the tocotrienols (Section 4.1). 

OH) 2 cholecalciferol Sterol Intestine Bone Facilitation of calcium and phosphorus absorption increase in bone resorption in conjunction with PTH... 

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. 

NPCILI is a protein with 42% identity with NPCl (J.P. Davies, 2000). Several lines of evidence indicate that NPCILI plays a role in the intestinal absorption of cholesterol and plant sterols (S.W. Altmann, 2004) [22]. NPCILI is found on the plasma membrane of enterocytes in the proximal jejunum. NPCILI homozygous knockout mice absorb significantly less cholesterol than control mice and are insensitive to the effects of ezetimibe, a cholesterol absorption inhibitor that lowers plasma LDL cholesterol levels. 

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. 

Recent data indicate that ezetimibe inhibits a specific transport process in jejunal enterocytes, which take up cholesterol from the lumen. The putative transport protein is Niemann-Pick Cl-hke 1 protein (NPCILI). In wild-type mice, ezetimibe inhibits cholesterol absorption by about 70% in NPCILI knockout mice, cholesterol absorption is 86% lower than in wild-type mice, and ezetimibe has no effect on cholesterol absorption. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. There is also a substantial reduction of plasma levels of plant sterols (campesterol and sitosterol concentrations are reduced by 48 and 41%, respectively), indicating that ezetimibe also inhibits intestinal absorption of plant sterols. 

Sterol-specific cytoplasmic receptor proteins (vitamin D receptor) mediate the biological action of vitamin D (9). The active hormone is transported from the cytoplasm to the nucleus via the vitamin D receptor, and as a result of the interaction of the hormone with target genes, a variety of proteins are produced that stimulate the transport of calcium in each of the target tissues. Active vitamin D works in concert with PTH to enhance active intestinal absorption of calcium, to stimulate bone resorption, and to prohibit renal excretion of calcium (2,9). If serum calcium or 1,25-calcitriol concentrations are elevated, then vitamin D 24-hydroxylase (in renal mitochondria) is activated to oxidize 25(OH)D3 to inactive 24,25-dihydroxy-cholecalciferol and to further oxidize active vitamin D to the inactive 1,24,25-trihydroxylated derivative. Both the 1,24,25-trihydroxylated and the 24,25-dihydroxylated products have been found to suppress PTH secretion as well. Several factors have been identified in the regulation of the biosynthesis of vitamin D, including low phosphate concentrations (stimulatory) as well as pregnancy and lactation (stimulatory). 

Like cholesterol, PS are absorbed in the proximal part of the small intestine after being incorporated into mixed micelles. Compared to cholesterol, the intestinal absorption of PS is low. While 40-60% of dietary cholesterol is absorbed, only about 5% of the PS are absorbed [18]. In addition, the efficiency of PS absorption is critically dependent on the structure of both sterol nucleus and side chain. For instance, the rate of plant sterol absorption was investigated in a human study... 

Chitosan also has hypocholesterolemic effects and acts as an adjuvant to weight loss in rat studies [31,32]. Studies have reported that chitosan reduced the concentration of plasma cholesterol in animals [33,34] and type If diabetes patients in combination with hypercholesterolemia [33]. This property is being attributed to the positive charge of the molecule that binds to fatty acids (released from consumed fat) and bile salt components, which results in disrupted lipid absorption in the gut [5]. Also, chitosan is dissolved in the stomach, emulsifying the fat and forming a gel in the intestine which entraps fat and prevents intestinal absorption [35,36]. Chitosan forms a floccule in the duodenum which entraps dietary oil [37]. However, these effects are still controversial [31,38,39]. Actually, van Bennekum et al. [32] suggested that the incorporation of chitosan in the diet of rats reduces cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. 

The mode of action of sitosterol, which differs in structure from cholesterol by possession of an ethyl group on C-24, has not been established. In contrast to cholesterol, intestinal absorption of sitosterol has been shown to take place in only very small quantities (Schoenheimer 1929,1932, Best 1956, Schettler 1961) and amounts to about 5% of administered sitosterol, (Gould 1955). According to one theory sitosterol interferes with the absorption of cholesterol. If cholesterol and sitosterol are administered simultaneously, the absorption of the former is markedly decreased (Hernandez et al. 1953) only one-third of the cholesterol is absorbed if both substances are administered in equal parts, while cholesterol absorption is nil when cholesterol and sitosterol are fed in the proportion of 1 7 (Pollak 1953). Mixed crystal formation may be responsible for this effect, as suggested by the in vivo and in vitro studies of Davis (1955) and of Hudson and co-workers (1959), who found crystals with an X-ray diffraction pattern different from either cholesterol or sitosterol, and suspected the presence of a less-dispersible compound. The assumption of Swell et al. (1954) that there is competitive inhibition of esterification of cholesterol by sitosterol, has been refuted by Blomstrand and Ahrens (1958), and the suggestion of Glover et al. (1957) of competition for acceptor lipoproteins is unproved. Gerson and Shorland (1963), on the basis of isotopic studies in rats, considered the effect of beta-sitosterol on cholesterol absorption to be less important, and discussed the effects of the sterol on cholesterol metabolism and on the cholesterol content of different tissues. 

This fundamental role of bile salts in the intestinal absorption of sterols is a reflection of the potential requirements for this cholesterol metabolites in various steps of intraluminal and epithelial cell mechanisms of cholesterol absorption (Figure 1), These include solubilization of cholesterol in the intestinal lumen by mixed micelles, containing biliary bile salts and phospholipids, and the products of triglyceride digestion modification of the intestinal surface barriers to cholesterol transfer, including the un-stirred water layer" and the mucin "coat" and the cellular esterification of cholesterol prior to incorporation of the resulting esters into the lipoprotein core lipids. 

The obligatory role of bile salts for intestinal absorption of cholesterol can be accounted for by multifaceted functions in the luminal, translocation and cellular phases of absorption. Micellar solubilization of unesterified cholesterol is a requisite for overall absorption of cholesterol into lymph. This increases by many-fold, the monomolecular form of sterol, and allows for efficient membrane translocation. 

Vitamin D has little influence on the serum calcium level in health, but in conditions of hypocalcsemia it raises the calcium and phosphate content of the serum, and promotes intestinal absorption of phosphorus and calcium. Solar and ultra-violet irradiation act by enabling the organism to manufacture vitamin D from its sterol precursor, if already present in the tissues. 

The practical development of plant sterol drugs as cholesterol-lowering agents will depend both on structural features of the sterols themselves and on the form of the administered agent. For example, the unsaturated sterol sitosterol is poorly absorbed in the human intestine, whereas sitostanol, the saturated analog, is almost totally unabsorbable. In addition, there is evidence that plant sterols administered in a soluble, micellar form (see page 261 for a description of micelles) are more effective in blocking cholesterol absorption than plant sterols administered in a solid, crystalline form. 

Irrespective of the physical form of the carotenoid in the plant tissue it needs to be dissolved directly into the bulk lipid phase (emulsion) and then into the mixed micelles formed from the emulsion droplets by the action of lipases and bile. Alternatively it can dissolve directly into the mixed micelles. The micelles then diffuse through the unstirred water layer covering the brush border of the enterocytes and dissociate, and the components are then absorbed. Although lipid absorption at this point is essentially complete, bile salts and sterols (cholesterol) may not be fully absorbed and are not wholly recovered more distally, some being lost into the large intestine. It is not known whether carotenoids incorporated into mixed micelles are fully or only partially absorbed. 

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

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