Studies on Intestinal Cholesterol Absorption in the Human

Borgström, Bengt

doi:10.1172/jci104100

Cited by 127 publications

(43 citation statements)

References 13 publications

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“…Furthermore, the expression levels of NPC1L1 mRNA and protein are relatively higher in the proximal small intestine of rats and relatively lower in the distal small intestine (54). Therefore, our results support the concept that the main sites of Ch absorption are the duodenum and proximal jejunum (55)(56)(57)(58). It is important to note that in the chow-fed mouse, the expression levels of Abcg5 and Abcg8 in the duodenum and jejunum are somewhat greater compared with those in the ileum as measured by Northern blot analysis (3,5,24).…”

Section: Discussionsupporting

confidence: 85%

Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters Abcg5 and Abcg8 in mice

Duan

Wang

2004

Journal of Lipid Research

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In the present study, we investigated whether intestinal sterol efflux transporters Abcg5 and Abcg8 play a major role in determining variations in cholesterol (Ch) absorption efficiency, and we compared the physiological functions of the duodenal, jejunal, and ileal Abcg5 and Abcg8 on the absorption of Ch and sitostanol in inbred mice challenged with various amounts of Ch, sitostanol, hydrophilic, or hydrophobic bile acids. We found that Abcg5 and Abcg8 in the jejunum and ileum, but not in the duodenum, were main factors in determining, in part, variations in Ch absorption efficiency. The jejunal and ileal Abcg5 and The small intestine is a unique organ that provides dietary and reabsorbed biliary cholesterol (Ch) to the body and plays a critical role in the regulation of whole-body Ch balance (1, 2). Because elevated plasma Ch concentrations are important risk factors for cardiovascular diseases, intensive studies have been carried out to search for physical-chemical, biochemical, and genetic determinants of intestinal Ch absorption. Recently, two independent groups (3, 4) used a microarray analysis of mouse intestine and liver genes upregulated by a liver X receptor (LXR) agonist, as well as a positional cloning approach to identify mutations in sitosterolemia patients in either member of an adjacent pair of genes, ABCG5 and ABCG8 , encoding ATP-binding cassette (ABC) transporters expressed in the liver and intestine. By studying their function and expression in some "manufactured" mouse strains treated with or without LXR agonists (5-9), it has been proposed that ABCG5 and ABCG8 could promote efflux of Ch and sitosterol (plant sterol) from the enterocyte back into the intestinal lumen for elimination and mediate biliary sterol secretion in the human. Although a very large number of polymorphic variants in both Abcg5 and Abcg8 among 20 strains of inbred mice have been identified (10), none of these mice showed any detectable levels of plasma sitosterol under chow diet (containing ‫ف‬ 0.01% sitosterol) conditions. Thus, whether the polymorphisms at the Abcg5 and Abcg8 genes and their expression levels in the intestine are an important determinant of intestinal Ch absorption efficiency in healthy inbred mice remains to be investigated. Furthermore, the autosomal recessive disorder sitosterolemia (11-13) is mainly characterized by hyperabsorption of Ch and sitosterol, and reduced secretion of these sterols into bile. In patients with sitosterolemia (14-17), the intestinal absorp-

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Section: Discussionsupporting

confidence: 85%

Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters Abcg5 and Abcg8 in mice

Duan

Wang

2004

Journal of Lipid Research

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“…The reduced cholesterol absorption efficiency observed in these animals is consistent with our previous hypothesis that efficient TAG digestion in the proximal intestine is necessary for cholesterol partitioning to micelles for subsequent absorption by enterocytes. The deficiency in PTL alone or in combination with CEL delays TAG hydrolysis to the distal intestine (1) where the cholesterol is less efficiently taken up (4,5). The lower fasting cholesterol levels observed in PTL Ϫ/Ϫ and PTL Ϫ/Ϫ ,CEL Ϫ/Ϫ mice consuming the Western-type diet (Table 1) is consistent with the reduced cholesterol absorption efficiency in these animals.…”

Section: ϫ/ϫmentioning

confidence: 99%

“…Dietary lipids, such as triacylglycerol (TAG), 4 phospholipids, cholesteryl esters, and retinyl esters must be cleaved by intestinal hydrolases before absorption. Thus, lipid hydrolases derived from the pancreas are central in the digestion and absorption of these dietary components.…”

mentioning

confidence: 99%

“…Second, whereas CEL Ϫ/Ϫ mice displayed dramatically reduced cholesteryl ester hydrolysis and absorption as expected (2), retinyl ester digestion and absorption were similar between CEL ϩ/ϩ and CEL Ϫ/Ϫ mice (3). The decrease in cholesterol absorption observed in the PTL Ϫ/Ϫ mice was attributed to PTL deficiency delaying dietary fat absorption to the distal small intestine (ileum) where intestinal cholesterol uptake is less efficient (4,5). However, the nearly normal absorption of TAG and retinyl esters in PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice suggested that more than one enzyme participates in the digestion of these lipids in vivo.…”

mentioning

confidence: 99%

“…Samples were obtained from mice consuming the low fat chow or the high fat/high cholesterol Western-type diet for 40 weeks after an overnight fast, except for the insulin levels, which were determined from 5 wild type, 4 …”

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confidence: 99%

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Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Gilham¹,

Labonté²,

Rojas

et al. 2007

Journal of Biological Chemistry

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Despite the fundamental importance that digestion, absorption, and subsequent trafficking of dietary fat, fat soluble vitamins, and cholesterol play in health and disease, details of the molecular events involved in these processes remain poorly described. Dietary lipids, such as triacylglycerol (TAG), 4 phospholipids, cholesteryl esters, and retinyl esters must be cleaved by intestinal hydrolases before absorption. Thus, lipid hydrolases derived from the pancreas are central in the digestion and absorption of these dietary components. The most abundant lipolytic enzymes secreted by the pancreas include pancreatic triglyceride lipase (PTL) and carboxyl ester lipase (CEL, formerly named cholesterol esterase). The principal enzyme involved in the hydrolysis of dietary TAG, thereby mediating its absorption, has generally been accepted as PTL. In contrast, the major role of CEL in the digestive tract is generally ascribed to digestion of cholesteryl esters and retinyl esters before their absorption.Recent studies with genetically modified mouse models designed to critically examine the role of pancreatic lipolytic enzymes in lipid digestion and transport revealed some unexpected findings. First, TAG absorption was altered very little, but free cholesterol absorption was reduced substantially in PTL Ϫ/Ϫ mice (1). Second, whereas CEL Ϫ/Ϫ mice displayed dramatically reduced cholesteryl ester hydrolysis and absorption as expected (2), retinyl ester digestion and absorption were similar between CEL ϩ/ϩ and CEL Ϫ/Ϫ mice (3). The decrease in cholesterol absorption observed in the PTL Ϫ/Ϫ mice was attributed to PTL deficiency delaying dietary fat absorption to the distal small intestine (ileum) where intestinal cholesterol uptake is less efficient (4, 5). However, the nearly normal absorption of TAG and retinyl esters in PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice suggested that more than one enzyme participates in the digestion of these lipids in vivo. In vitro studies examining lipolytic activities in pancreatic extracts from PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice provided insights to the identity of enzymes responsible for TAG and retinyl ester hydrolysis. In these studies pancreatic extracts from PTL Ϫ/Ϫ mice were shown to contain robust TAG hydrolytic activity, albeit at lower levels than those observed in pancreatic extracts from wild type mice. Importantly, the TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas was dependent on the presence of taurocholate, whereas taurodeoxycholate was found to be ineffective (1). This selectivity of trihydroxylated bile salt for TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas is consistent with the trihdroxy-but not dihydroxy-bile salt dependence of CEL (6), thus * This work was supported by National Institutes of Health Grant DK067416.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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The Role of Bile Acids in the Overall Regulation of Steroid Metabolism

Wilson¹

1972

Arch Intern Med

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Studies on Intestinal Cholesterol Absorption in the Human

Cited by 127 publications

References 13 publications

Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters Abcg5 and Abcg8 in mice

Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters Abcg5 and Abcg8 in mice

Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

The Role of Bile Acids in the Overall Regulation of Steroid Metabolism

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