Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

Fuchs, Michael; Ivandic, Boris; Müller, Oliver; Schalla, Carmen; Scheibner, Jürgen; Bartsch, Petra; Stange, Eduard F.

doi:10.1053/jhep.2001.24373

Cited by 53 publications

(49 citation statements)

References 66 publications

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“…A similar increase in the proportion of large HDL 1 particles is also observed with partial (40) or total (41) SRBI deficiency. Consistent with our finding, SRBI expression is induced in the liver of C57L/J mice upon cholic acid feeding (38). In the present report, we also showed that cholic acid positively regulates SRBI mRNA and protein expression in the liver of wild-type but not in that of FXR(Ϫ/Ϫ) mice.…”

Section: Discussionsupporting

confidence: 93%

“…Consistent with our data, Fuchs et al (38) demonstrated that gallstonesusceptible C57L/J or gallstone-resistant AKR mice had similar apoA-I mRNA and protein levels when placed either on chow or on 0.5% cholic acid diet. In contrast, Claudel et al (14) reported that administration of the FXR agonist taurocholate repressed apoA-I expression in human hepatoma HepG2 cells as well as in human apoA-I transgenic mice.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

Lambert¹,

Amar²,

Guo³

et al. 2003

Journal of Biological Chemistry

352

265

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

Lambert¹,

Amar²,

Guo³

et al. 2003

Journal of Biological Chemistry

352

265

View full text Add to dashboard Cite

“…3D illustrates that the increase (2.4-fold) of SR-BI expression in Abcb11 transgenic mice is 60% greater than the increase of SR-BI expression in wild-type mice (p Ͻ 0.01). These data are also consistent with previous data reporting a significant hepatic induction of the SR-BI receptor in response to the lithogenic diet (22). In contrast, the expression levels of Abcb11 (Fig.…”

Section: Expression Of Bile Salt and Cholesterol Metabolic Andsupporting

confidence: 93%

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Figge

Lammert

Paigen

et al. 2004

Journal of Biological Chemistry

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Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BACAbcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7␣-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.

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“…ApoB-containing lipoproteins (LDL and very-low-density lipoprotein) from the circulation, while SRB1 promotes selective uptake of HDL-cholesterol into the liver (9). Although increases in the expression of these genes may be expected to increase cholesterol secretion into the bile, the expression of Cyp27 was also elevated in the EX mice.…”

Section: Exercise and Gallstonesmentioning

confidence: 99%

Endurance exercise training reduces gallstone development in mice

Wilund¹,

Feeney²,

Tomayko³

et al. 2008

Journal of Applied Physiology

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Wilund KR, Feeney LA, Tomayko EJ, Chung HR, Kim K. Endurance exercise training reduces gallstone development in mice. J Appl Physiol 104: 761-765, 2008. First published January 10, 2008 doi:10.1152/japplphysiol.01292.2007.-Gallstones form when the ratio of bile cholesterol to bile acids and phospholipids is elevated, causing cholesterol to precipitate. Physical inactivity is hypothesized to increase gallstone development, but experimental evidence supporting this is lacking, and potential mechanisms for the antilithogenic effects of exercise have not been described. The purpose of this study was to examine the effect of endurance exercise training on gallstone formation and the expression of genes involved in bile cholesterol metabolism in gallstone-sensitive (C57L/J) mice. At 10 wk, 50 male mice began a lithogenic diet and were randomly assigned to an exercise-training (EX) or sedentary (SED) group (n ϭ 25 per group). Mice in the EX group ran on a treadmill at ϳ15 m/min for 45 min/day for 12 wk. At the time animals were euthanized, gallstones were collected, pooled by group, and weighed. The weight of the gallstones was 2.5-fold greater in the SED mice compared with EX mice (143 vs. 57 mg, respectively). In the EX mice, hepatic expression of the low-density lipoprotein receptor (LDLr), scavenger receptor class B type 1 (SRB1), and sterol 27 hydroxylase (Cyp27) was increased by ϳ2-fold (P Ͻ 0.05 for each). The LDLr and SRB1 increase cholesterol clearance by low-density lipoprotein and high-density lipoprotein particles, respectively, while Cyp27 promotes the catabolism of cholesterol to bile acids. Taken together, these data indicate that exercise promotes changes in hepatic gene expression that increase cholesterol uptake by the liver but simultaneously increase the catabolism of cholesterol to bile acids, effectively reducing cholesterol saturation in the bile. This suggests a mechanism by which exercise improves cholesterol clearance from the circulation while simultaneously inhibiting gallstone formation.

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Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

Cited by 53 publications

References 66 publications

The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Endurance exercise training reduces gallstone development in mice

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