Loci on chromosomes 14 and 2, distinct from ABCG5/ABCG8, regulate plasma plant sterol levels in a C57BL/6J × CASA/Rk intercross

Sehayek, Ephraim; Duncan, Elizabeth M.; Lütjohann, Dieter; Bergmann, Klaus von; Ono, Jennie G.; Batta, Ashok K.; Salen, Gerald; Breslow, Jan L.

doi:10.1073/pnas.212640599

Cited by 28 publications

(22 citation statements)

References 14 publications

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“…Thus the remaining sterol secretion in Abcg5-deficient mice is independent from LXR-activated systems. Interestingly, Sehayek and colleagues (31) reported that Abcg5/Abcg8-independent loci regulate plasma plant sterol levels in mice. This further supports the hypothesis that other mechanisms than Abcg5/Abcg8-mediated transport exist to regulate sterol homeostasis.…”

Section: Bladder Of Abcg5mentioning

confidence: 99%

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Plösch¹,

Veen²,

Havinga³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Plö sch, Torsten, Jelske N. van der Veen, Rick Havinga, Nicolette C. A. Huijkman, Vincent W. Bloks, and Folkert Kuipers. Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice. Am J Physiol Gastrointest Liver Physiol 291: G414 -G423, 2006. First published April 13, 2006; doi:10.1152/ajpgi.00557.2005.-The ATP-binding cassette (ABC) half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates the secretion of plant sterols and cholesterol by hepatocytes into bile and their apical efflux from enterocytes. We addressed the putative rate-controlling role of Abcg5/Abcg8 in hepatobiliary cholesterol excretion in mice during (maximal) stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output rates were reduced by 82% and 35%, respectively, in chow-fed Abcg5 Ϫ/Ϫ mice compared with wild-type mice. When mice were infused with the hydrophilic BS tauroursodeoxycholate, similar relative increases in bile flow, BS output, PL output, and total sterol output were observed in wild-type, Abcg5 ϩ/Ϫ , and Abcg5 Ϫ/Ϫ mice. Maximal cholesterol and PL output rates in Abcg5 Ϫ/Ϫ mice were only 15% and 69%, respectively, of wild-type values. An infusion of increasing amounts of the hydrophobic BS taurodeoxycholate increased cholesterol excretion by 3.0-and 2.4-fold in wild-type and Abcg5 Ϫ/Ϫ mice but rapidly induced cholestasis in Abcg5 Ϫ/Ϫ mice. Treatment with the liver X receptor (LXR) agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (fourfold), concomitant with the induction of Abcg5/Abcg8 expression, but not in Abcg5 Ϫ/Ϫ mice. In a separate study, mice were fed chow containing 1% (wt/wt) cholesterol. As expected, hepatic expression of Abcg5 and Abcg8 was strongly induced (fivefold and fourfold) in wild-type but not LXR-␣-deficient (Lxra Ϫ/Ϫ ) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type mice and 2.0-fold in Lxra Ϫ/Ϫ mice, upon cholesterol feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, our data demonstrate that Abcg5/Abcg8 heterodimer-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.ATP-binding cassette transporter; bile formation; biliary lipids; canalicular transport MUTATIONS in the ATP binding-cassette (ABC) half-transporters ABCG5 and ABCG8 cause sitosterolemia (3, 23), which is characterized by the accumulation of plant sterols in the body (4). Data indicate that ABCG5 and ABCG8, which are highly expressed in the liver and small intestine, heterodimerize into a functional complex (3,12). Mutations in either one of the genes cause the biochemical hallmarks of the disease in humans (3, 23) as well as in mouse models (18,27). The daily intake of plant sterols, i.e., sitosterol and campesterol, from a "Western-type" diet is in the same o...

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Section: Bladder Of Abcg5mentioning

confidence: 99%

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Plösch¹,

Veen²,

Havinga³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Tail tips from parental, F1, F2, and N2-N6 animals were digested with proteinase K, DNA-precipitated with ethanol, and PCR genotyped for 255 microsatellite markers polymorphic between C57BL/6J and CASA/Rk using fluorescently labeled primers as described previously (15). Allele scores were analyzed using ABI Genotyper 3.6 NT software.…”

Section: Genotypingmentioning

confidence: 99%

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culprit

Sehayek

Hagey

Fung

et al. 2006

Journal of Lipid Research

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An intercross between C57BL/6J and CASA/Rk mice was used to study the genetics of biliary bile acid composition. In parental strains, male C57BL/6J mice had significantly higher cholic acid (CA; 14%) and lower b-muricholic acid (bMC; 27%) than CASA/Rk mice, whereas females did not differ. However, quantitative trait locus analysis of F2 mice revealed no significant chromosome 9 loci in males but loci in females on chromosome 9 for percentage CA (%CA) at 72 centimorgan (cM) [logarithm of the odds (LOD) 5.89] and %bMC at 54 cM (LOD 4.09). Chromosome 9 congenic and subcongenic strains representing CASA/Rk intervals 38-73 cM (9KK) and 68-73 cM (9DKK) on the C57BL/6J background were made. In 9KK and 9DKK males, %CA was increased and %bMC was unchanged, whereas in 9KK but not 9DKK females, %CA was increased and %bMC was decreased. Sterol 12a-hydroxylase (Cyp8b1) channels bile acid precursors into CA and maps at chromosome 9 (73 cM). However, there was no significant difference in Cyp8b1 mRNA or enzymatic activity between parental mice, parental-congenic-subcongenic mice, or highlow biliary %CA F2 mice. In summary, two chromosome 9 loci control sexually dimorphic effects on biliary bile acid composition: a distal (68-73 cM) major determinant in males, and a more proximal (38-68 cM) major determinant in females. In this intercross, Cyp8b1, a strong candidate, does not appear to be responsible. In humans and mice, biliary bile acid composition affects the enterohepatic metabolism of lipids, including the synthesis and transport of bile acids across hepatocytes, the excretion of biliary lipids, and the absorption of sterols from the intestines (1-6). In humans, the two major primary bile acids are chenodeoxycholic acid (CDCA), a dihydroxy bile acid, and cholic acid (CA), a trihydroxy bile acid. The difference between them is hydroxylation of the 12 carbon of the sterol ring, which is carried out by the enzyme sterol 12a-hydroxylase (CYP8B1). As a result, CDCA is more hydrophobic and CA is more hydrophilic. In mice, CA is one of the major primary bile acids; it is formed by CYP8B1-mediated 12 hydroxylation. Muricholic acids comprise the other major murine bile acids, and they are formed from CDCA by 6 hydroxylation and 7 epimerization to generate a-and b-muricholic acid (bMC), with bMC predominating. bMC is even more hydrophilic than CA. Although the mouse does not have CDCA as a major species, it is possible to use this model to identify genes that influence the 12 hydroxylation pathway and uptake of bile acids from the intestines by studying the proportions of CA and bMC in bile. Identifying the genes that influence 12 hydroxylation and bile acid uptake from the intestines is particularly important because they determine the proportions of CA and CDCA and hence the hydrophobicity of the bile acid pool in humans.In humans, the proportions of CA and CDCA vary between individuals (7, 8), and there is some evidence for genetic control. For example, studies in monozygotic and dizygotic twins found a significant pair-...

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“…We previously published the linkage map on chromosome 14 ( 4,5 ). This map is characterized by two peaks, one at D14Mit18 and the other at D14Mit123, that map at 48.4 Mb and 66.8 Mb, respectively.…”

Section: Heritability Mode Of Cholesterol Absorption In Subcongenic Gmentioning

confidence: 99%

“…Interestingly, generation of two subcongenic strains, 14PKK and 14DKK, which consisted of the centromeric 20.8 Mb and telomeric 70. 4 Mb of the 14KK interval, respectively, displayed decreased cholesterol absorption in both genders ( 5 ). Here we describe the fi ne-mapping of the 14DKK subcongenic interval.…”

mentioning

confidence: 92%

“…This effort allowed mapping of a locus on chromosome 14 that we designated Plast14 with a linkage map that displayed two broad peaks at markers D14Mit18 (48.4 Mb) and D14Mit123 (66.8 Mb) ( 4 ). To validate the effect of the Plast14 locus, we fi rst generated a congenic strain that was designated 14KK and consisted of a chromosome 14 CASA/Rk 100.1 Mb interval introgressed onto the C57BL/6J genetic background.…”

mentioning

confidence: 99%

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Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine

Wong

Altemus

Hester

et al. 2013

Journal of Lipid Research

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Loci on chromosomes 14 and 2, distinct from ABCG5/ABCG8, regulate plasma plant sterol levels in a C57BL/6J × CASA/Rk intercross

Cited by 28 publications

References 14 publications

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culprit

Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine

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