Genetic factors at the enterocyte level account for variations inintestinal cholesterol absorption efficiency among inbred strains of mice

Wang, David Q.–H.; Paigen, Beverly; Carey, Martin C.

doi:10.1016/s0022-2275(20)31508-x

Cited by 75 publications

(13 citation statements)

References 69 publications

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“…As can be inferred from these definitions, cholesterol absorption is a multistep process that is regulated by multiple genes. 16,17 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.…”

Section: Physiology Of Intestinal Cholesterol Absorptionmentioning

confidence: 99%

“…2,3 It has been found that, following an intragastric dose of cholesterol, the transport of cholesterol mass and radioactivity in intestinal lymph increases rapidly and peaks after 6 -8 hours. 16,17,32,33 After entering the enterocytes, approximately half of the cholesterol molecules move to the endoplasmic reticulum where they are esterified by acyl-CoA:cholesterol acyltransferase (ACAT) before incorporation into nascent chylomicron particles. Of special note is that essentially all cholesterol that moves from the intestinal lumen into enterocytes is unesterified; in contrast, cholesterol secreted into intestinal lymph following a cholesterol-rich meal is approximately 70%-80% esterified.…”

Section: Physiology Of Intestinal Cholesterol Absorptionmentioning

confidence: 99%

“…Interindividual and interstrain variations in intestinal cholesterol absorption efficiency occur in primates, 47,48 including humans, 4,49 -52 as well as in inbred strains of mice, 17,[53][54][55][56] rats, 57 and rabbits. 58,59 These observations strongly suggest that intestinal cholesterol absorption is regulated by multiple genes because diet, the key environmental factor, is controlled in these studies.…”

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

“…Gylling and Miettinen 60 examined cholesterol absorption by a fecal dual-isotope ratio method in probands with very high and low plasma cholestanol levels (a plant sterol that correlates with cholesterol absorption) and their siblings; siblings of the higher-absorbing probands display significantly higher percentages (49% Ϯ 2%) of cholesterol absorption than siblings of the lower absorbing probands (37% Ϯ 3%). Recently, it is observed 17 that there are significant differences in cholesterol absorption efficiency measured by plasma, fecal, and lymphatic methods among 12 inbred strains of mice: Ͻ25% in AKR/J, C3H/J, and A/J strains; 25%-30% in SJL/J, DBA/2J, BALB/cJ, SWR/J, and SM/J strains; and 31%-40% in C57L/J, C57BL/6J, FVB/J, and 129/SvJ strains. Especially, when dietary factors are controlled by feeding chow containing trace (Ͻ0.02%) amounts of cholesterol, cholesterol absorption efficiency in C57L/J inbred mice with intact enterohepatic circulation of bile salts is significantly higher than that in AKR/J inbred mice, as measured by 4 independent methods, ie, the plasma and the fecal dual-isotope ratio methods, the lymphatic transport of cholesterol, and the mass balance method.…”

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

“…Especially, when dietary factors are controlled by feeding chow containing trace (Ͻ0.02%) amounts of cholesterol, cholesterol absorption efficiency in C57L/J inbred mice with intact enterohepatic circulation of bile salts is significantly higher than that in AKR/J inbred mice, as measured by 4 independent methods, ie, the plasma and the fecal dual-isotope ratio methods, the lymphatic transport of cholesterol, and the mass balance method. 16,17 When these studies were repeated in mice with chronic biliary fistulae but in the setting of duodenal infusion of taurocholate and egg yolk lecithin, the marked differences in intestinal cholesterol absorption efficiency still persist between the 2 mouse strains. 16,17 Furthermore, cholesterol absorption in (AKR/JϫC57L/ J)F 1 progeny mimics the higher absorbing parental strain C57L/J, suggesting that high cholesterol absorption is a dominant trait in mice.…”

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

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New Insights Into the Genetic Regulation of Intestinal Cholesterol Absorption

2005

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Section: Physiology Of Intestinal Cholesterol Absorptionmentioning

confidence: 99%

Section: Physiology Of Intestinal Cholesterol Absorptionmentioning

confidence: 99%

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

Section: Genetic Factors On Variations In the Efficiency Of Intestina...mentioning

confidence: 99%

See 3 more Smart Citations

New Insights Into the Genetic Regulation of Intestinal Cholesterol Absorption

2005

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Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Wang

2005

Hepatology

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It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

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Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8 −/− mice†‡

et al. 2007

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Sitosterolemia is caused by mutations in either ABCG5 or ABCG8, but simultaneous mutations of these genes have never been observed. To explore whether ABCG8, the sterol efflux (hemi-)transporter, plays a major role in determining intestinal absorption efficiency and hepatic secretion rates of cholesterol and sitostanol, we performed direct measurements of the absorption and lymphatic transport of these sterols in mice with chronic biliary and lymphatic fistulae, as well as the transport rates of radiolabeled cholesterol and sitostanol from plasma high-density lipoprotein (HDL) into bile in male Abcg8 ؊/؊ and wild-type mice. We observed that the absorption and lymphatic transport rates of radiolabeled cholesterol and sitostanol were increased by Ϸ40% and Ϸ500%, respectively, in Abcg8 S itosterolemia is a rare autosomal, recessively inherited disorder that is characterized mainly by elevated plasma levels of plant sterols (phytosterols) and with normal or only moderately increased cholesterol levels. 1 Sitosterolemic patients display hyperabsorption of cholesterol and phytosterols and reduced secretion of these sterols into bile. 2,3 Patel et al. 4 were the first to map the sitosterolemia locus, STSL, to human chromosome 2p21, between D2S2294 and D2S2298. Using a positional cloning approach as well as microarray analysis of murine complementary DNAs from intestines and livers of mice treated with a liver X receptor (LXR) agonist, 2 groups 5,6 independently identified the adjacent genes, ABCG5 and ABCG8, encoding adenosine triphosphatebinding cassette (ABC) hemi-transporters that are mutated in sitosterolemia. Unlike other ABC transporters that encode proteins with 12-transmembrane domains, these 2 proteins function as a unique heterodimer forming a 12-transmembrane protein complex essential for sterol transport activity. 7 Heterodimerization of ABCG5 and ABCG8 is also necessary for their translocation from endoplasmic reticulum to the plasma membrane. 8 Based on these observations, as well as the similarity of the clinical and biochemical phenotypes, it has been proposed that both ABCG5 and ABCG8 function as obligate heterodimers in the transmembrane "flipping" of sterols. 9 A mouse model with disruption of both Abcg5 and Abcg8 results in a phenotype similar to that of human disease. 10Abbreviations: ABC, adenosine triphosphate-binding cassette (transporter); HDL, high-density lipoprotein; LXR, liver X receptor. From the

show abstract

Genetic factors at the enterocyte level account for variations inintestinal cholesterol absorption efficiency among inbred strains of mice

Cited by 75 publications

References 69 publications

New Insights Into the Genetic Regulation of Intestinal Cholesterol Absorption

New Insights Into the Genetic Regulation of Intestinal Cholesterol Absorption

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8 −/− mice†‡

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