New Insights Into the Genetic Regulation of Intestinal Cholesterol Absorption
2005; Elsevier BV; Volume: 129; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2004.11.017
ISSN1528-0012
AutoresFrank Lammert, David Q.‐H. Wang,
Tópico(s)Diabetes Treatment and Management
ResumoThe small intestine is a unique organ providing dietary and reabsorbed biliary cholesterol to the body. However, the molecular mechanisms whereby cholesterol is absorbed have not yet been fully understood. Recent research suggests that the newly identified Niemann-Pick C1-like 1 protein (NPC1L1) is expressed at the apical surface of enterocytes and plays a critical role in the absorption of intestinal cholesterol. Furthermore, adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8 represent apical sterol export pumps that promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. This provides an explanation why cholesterol absorption is a selective process, with plant sterols and other noncholesterol sterols being absorbed poorly or not at all. These findings strongly support the concept that cholesterol absorption is a multistep process, which is regulated by multiple genes at the enterocyte level. The absorption efficiency of cholesterol is most likely determined by the net effect between influx and efflux of intraluminal cholesterol molecules across the brush border of the enterocyte. Combination therapy using a novel, specific, and potent cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and HMG-CoA reductase inhibitors (statins) offers an efficacious new approach to the prevention and treatment of hypercholesterolemia. The small intestine is a unique organ providing dietary and reabsorbed biliary cholesterol to the body. However, the molecular mechanisms whereby cholesterol is absorbed have not yet been fully understood. Recent research suggests that the newly identified Niemann-Pick C1-like 1 protein (NPC1L1) is expressed at the apical surface of enterocytes and plays a critical role in the absorption of intestinal cholesterol. Furthermore, adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8 represent apical sterol export pumps that promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. This provides an explanation why cholesterol absorption is a selective process, with plant sterols and other noncholesterol sterols being absorbed poorly or not at all. These findings strongly support the concept that cholesterol absorption is a multistep process, which is regulated by multiple genes at the enterocyte level. The absorption efficiency of cholesterol is most likely determined by the net effect between influx and efflux of intraluminal cholesterol molecules across the brush border of the enterocyte. Combination therapy using a novel, specific, and potent cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and HMG-CoA reductase inhibitors (statins) offers an efficacious new approach to the prevention and treatment of hypercholesterolemia. Cholesterol homeostasis is mainly maintained by balancing intestinal cholesterol absorption and endogenous cholesterol synthesis with excretion of biliary cholesterol and bile salts. Because elevated serum cholesterol levels are an important risk factor for cardiovascular diseases,1Grundy S.M. Cleeman J.I. Merz C.N. Brewer Jr, H.B. Clark L.T. Hunninghake D.B. Pasternak R.C. Smith Jr, S.C. Stone N.J. Coordinating Committee of the National Cholesterol Education Program; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Arterioscler Thromb Vasc Biol. 2004; 24: e149-e161Google Scholar extensive studies have been carried out to identify genetic, physical-chemical, and biochemical determinants of intestinal cholesterol absorption.2Wang D.Q.-H. New concepts of mechanisms of intestinal cholesterol absorption.Ann Hepatol. 2003; 2: 113-121Google Scholar, 3Turley S.D. Dietschy J.M. Sterol absorption by the small intestine.Curr Opin Lipidol. 2003; 14: 233-240Google Scholar Furthermore, the cholesterol carried in low-density lipoprotein (LDL) is derived principally from de novo synthesis and absorption from the diet. In humans, there is a significant and positive correlation between the level of serum LDL-cholesterol and the efficiency of intestinal cholesterol absorption.4Kesäniemi Y.A. Miettinen T.A. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population.Eur J Clin Invest. 1987; 17: 391-395Google Scholar Thus, pharmacologic control of intestinal cholesterol absorption is potentially an effective way of lowering serum LDL-cholesterol concentrations in the general population. Recent revised treatment guidelines1Grundy S.M. Cleeman J.I. Merz C.N. Brewer Jr, H.B. Clark L.T. Hunninghake D.B. Pasternak R.C. Smith Jr, S.C. Stone N.J. Coordinating Committee of the National Cholesterol Education Program; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Arterioscler Thromb Vasc Biol. 2004; 24: e149-e161Google Scholar emphasize that individuals at substantial risk for atherosclerosis or patients with cardiovascular diseases should meet defined targets for LDL-cholesterol levels, which has strikingly increased the number of individuals who need cholesterol-lowering therapy. Dietary plant sterols at a dose of 2 g/day have been recommended as adjunctive lifestyle treatment for hypercholesterolemia.5Maki K.C. Davidson M.H. Umporowicz D.M. Schaefer E.J. Dicklin M.R. Ingram K.A. Chen S. McNamara J.R. Gebhart B.W. Ribaya-Mercado J.D. Perrone G. Robins S.J. Franke W.C. 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Simvastatin Atorvastatin HDL Study GroupA comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial.Curr Med Res Opin. 2001; 17: 43-50Google Scholar More recently, the discovery and development of ezetimibe,10Rosenblum S.B. Huynh T. Afonso A. Davis Jr, H.R. Yumibe N. Clader J.W. Burnett D.A. Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235) a designed, potent, orally active inhibitor of cholesterol absorption.J Med Chem. 1998; 41: 973-980Google Scholar, 11Burnett D.A. Caplen M.A. Davis Jr, H.R. Burrier R.E. Clader J.W. 2-Azetidinones as inhibitors of cholesterol absorption.J Med Chem. 1994; 37: 1733-1736Google Scholar a novel, selective, and potent inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol, opens a new door to the treatment of hypercholesterolemia.12Knopp R.H. Dujovne C.A. Le Beaut A. Lipka L.J. Suresh R. Veltri E.P. Ezetimbe Study GroupEvaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia a pooled analysis from two controlled phase III clinical studies.Int J Clin Pract. 2003; 57: 363-368Google Scholar, 13Dujovne C.A. Bays H. Davidson M.H. Knopp R. Hunninghake D.B. Stein E.A. Goldberg A.C. Jones P. Lipka L.J. Cuffie-Jackson C. Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461 results of a multicenter dose-ranging study.J Clin Pharmacol. 2001; 41: 70-78Google Scholar, 14Bays H.E. Moore P.B. Drehobl M.A. Rosenblatt S. Toth P.D. Dujovne C.A. Knopp R.H. Lipka L.J. Lebeaut A.P. Yang B. Mellars L.E. Cuffie-Jackson C. Veltri E.P. Ezetimibe Study GroupEffectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia pooled analysis of two phase II studies.Clin Ther. 2001; 23: 1209-1230Google Scholar, 15Dujovne C.A. Ettinger M.P. McNeer J.F. Lipka L.J. LeBeaut A.P. Suresh R. Yang B. Veltri E.P. Ezetimbe Study GroupEfficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.Am J Cardiol. 2002; 90: 1092-1097Google Scholar This review will focus on the recent progress in the molecular mechanisms of cholesterol absorption and pharmacologic approaches to inhibit the absorption process. “Intestinal absorption of cholesterol” is most accurately defined as the transfer of intraluminal cholesterol into intestinal or thoracic duct lymph. Conceptually, absorption needs to be distinguished from “uptake of cholesterol,” which refers to entry of cholesterol into intestinal absorptive cells. As can be inferred from these definitions, cholesterol absorption is a multistep process that is regulated by multiple genes.16Wang D.Q.-H. Carey M.C. Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse an analysis of direct versus indirect methodologies.J Lipid Res. 2003; 44: 1042-1059Google Scholar, 17Wang D.Q.-H. Paigen B. Carey M.C. Genetic factors at the enterocyte level account for variations in intestinal cholesterol absorption efficiency among inbred strains of mice.J Lipid Res. 2001; 42: 1820-1830Abstract Full Text Full Text PDF Google Scholar Cholesterol enters the lumen of the small intestine from 3 sources: diet, bile, and intestinal epithelial sloughing. The average daily intake of cholesterol in the Western diet is approximately 300–500 mg. Bile provides 800–1200 mg cholesterol per day to the intraluminal pool. The turnover of intestinal mucosal epithelium establishes a third source of intraluminal cholesterol, which is estimated to contribute 300 mg cholesterol per day. Although the entire length of the small intestine has the capability to absorb cholesterol from the lumen, the main sites of absorption are the duodenum and proximal jejunum. Cholesterol absorption begins in the stomach when dietary constituents are mixed with lingual and gastric enzymes. The stomach also regulates the delivery of gastric chyme to the duodenum where it is mixed with bile and pancreatic juice. This process continues within the lumen of the small intestine. Some of the lipolytic products, including cholesterol, are nearly insoluble in a pure aqueous system and are therefore dependent on the solubilizing properties of bile salt solutions.18Hofmann A.F. Borgström B. Physico-chemical state of lipids in intestinal content during their digestion and absorption.Gastroenterology. 1963; 21: 43-50Google Scholar, 19Hofmann A.F. Borgström B. 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Bile salts are biologic amphipathic detergents and can spontaneously form aggregates, ie, simple micelles, when present above a critical micellar concentration. Although simple micelles are able to dissolve lipids,23Hofmann A.F. Small D.M. Detergent properties of bile salts correlation with physiological function.Annu Rev Med. 1967; 18: 333-376Google Scholar cholesterol is only sparingly soluble in bile salt solutions. The addition of phospholipid or monoacylglyceride to bile salt solutions strikingly augments the solubility of cholesterol by forming mixed micelles.24Wang D.Q.-H. Carey M.C. Complete mapping of crystallization pathways during cholesterol precipitation from model bile Influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems.J Lipid Res. 1996; 37: 606-630Abstract Full Text PDF Google Scholar, 25Eckhardt E.R. Wang D.Q.-H. Donovan J.M. 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Hernell O. Stafford R.J. Carey M.C. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 1. Phase behavior and aggregation states of model lipid systems patterned after aqueous duodenal contents of healthy adult human beings.Biochemistry. 1990; 29: 2028-2040Google Scholar, 27Hernell O. Staggers J.E. Carey M.C. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings.Biochemistry. 1990; 29: 2041-2056Google Scholar This liquid crystalline phase provides an accessible source of cholesterol and other lipids for continuous formation and modification of mixed micelles in the presence of bile salts. Before cholesterol molecules in the small intestinal lumen can interact with a possible cholesterol transporter(s) for uptake and subsequent transport across the brush border of the enterocyte, they must pass through a diffusion barrier that is located at the intestinal lumen-membrane interface, which may alter the kinetics of cholesterol absorption. This barrier includes an unstirred water layer and a surface mucous coat. Furthermore, the importance of the intestinal mucous coat as a diffusion-limiting barrier has been emphasized because cholesterol molecules could be extensively bound to surface mucins prior to transfer into the enterocyte. It has been observed that physiologic levels of the epithelial mucin encoded by the Muc1 gene are necessary for normal intestinal uptake and absorption of cholesterol in mice.28Wang H.H. Afdhal N.H. Gendler S.J. Wang D.Q.-H. Lack of the intestinal Muc1 mucin impairs cholesterol uptake and absorption but not fatty acid uptake in Muc1−/− mice.Am J Physiol. 2004; 287: G547-G554Google Scholar Because cholesterol absorption efficiency is reduced by ∼50% in Muc1-deficient mice, there may be alternative pathways for cholesterol absorption. Furthermore, uptake and absorption of cholesterol but not fatty acids is decreased in Muc1 knockout mice because the movement of big, rigid molecules such as cholesterol crossing the cell membrane is different from that of smaller, less rigid, and space-occupying molecules such as fatty acids. Because the lipid-protein interaction and structural assembly of proteins may influence the kinetics of net cholesterol movement across the cell membrane of enterocyte, it is crucial to investigate how the structural protein integrity or assembly at the level of the cell membrane is maintained during the intestinal absorption of cholesterol. In addition, the unstirred water layer, a series of water lamellae at the interface between the bulk water phase of the lumen and the apical membrane of the enterocyte, is considered to be an important barrier through which a cholesterol molecule in the bulk phase must pass to be absorbed.29Dietschy J.M. Sallee V.L. Wilson F.A. Unstirred water layers and absorption across the intestinal mucosa.Gastroenterology. 1971; 61: 932-934Google Scholar, 30Lukie B.E. Westergaard H. Dietschy J.M. Validation of a chamber that allows measurement of both tissue uptake rates and unstirred layer thicknesses in the intestine under conditions of controlled stirring.Gastroenterology. 1974; 67: 652-661Google Scholar Diffusion through the unstirred water layer is a relatively slow process for cholesterol that is only minimally soluble in aqueous systems. 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