The rate of biliary cholesterol secretion in high-and low-responding rhesus monkeys

The effects of clofibrate, cholestyramine, and neomycin on hepatobiliary lipid metabolism were studied in adult rhesus monkeys in metabolic steady state with intact but exteriorized enterohepatic circulations. Clofibrate (30 mg/kg, id) had no effect on lipid secretion while cholestyramine (150 mg/kg, id) decreased biliary cholesterol secretion rate from 0.19 ± 0.03 to 0.13 ± 0.02 mmol/24 h, p < 0.05. Neomycin (30 mg/kg, id) decreased bile flow from 216 ± 10 to 191 ± 7 mL/24 h, p < 0.05, and tended only to decrease bile salt and phospholipid secretion rates. Cholestyramine decreased cholesterol composition from 1.81 ± 0.22 to 1.30 ± 0.22 mol%, p < 0.05, while clofibrate and neomycin had insignificant effects. Cholestyramine and neomycin decreased bile salt pool size from 1 ± 0.1 to 0.77 ± 0.15 and from 1.45 ± 0.16 to 1.13 ± 0.21 mmol, p < 0.05, respectively, while clofibrate had no effect. Bile salt synthetic rate was increased only by cholestyramine, i.e., from 0.63 ± 0.04 to 1.48 ± 0.26 mmol/24 h, p < 0.01. Concomitant cholesterol turnover studies revealed that cholestyramine increased the production rate and excretion of cholesterol in the rapidly miscible cholesterol pool and increased the transfer of cholesterol from slow to rapidly miscible pools. Neomycin, on the other hand, decreased the size of the rapidly miscible pool by decreasing production rate without affecting the size of the slowly miscible pool, while clofibrate had insignificant effects.

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Biliary cholesterol secretion and bile acid formation in the hamster: the role of newly synthesized cholesterol.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)41183-6 ◽

1994 ◽

Vol 35 (4) ◽

pp. 690-697

Author(s):

J Scheibner ◽

M Fuchs ◽

E Hörmann ◽

G Tauber ◽

E F Stange

Keyword(s):

Bile Acid ◽

Acid Formation ◽

Biliary Cholesterol ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

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Evaluation of an isotope ratio method for measuring biliary cholesterol secretion.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)37930-x ◽

1983 ◽

Vol 24 (7) ◽

pp. 854-860

Author(s):

J R Crouse ◽

M D Wilson ◽

D S Weaver

Keyword(s):

Isotope Ratio ◽

Ratio Method ◽

Biliary Cholesterol ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

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Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice

Journal of Hepatology ◽

10.1016/s0168-8278(03)00093-x ◽

2003 ◽

Vol 38 (6) ◽

pp. 710-716 ◽

Cited By ~ 66

Author(s):

Astrid Kosters ◽

Raoul J.J.M. Frijters ◽

Frank G. Schaap ◽

Edwin Vink ◽

Torsten Plösch ◽

...

Keyword(s):

Atp Binding ◽

Biliary Cholesterol ◽

Hepatic Expression ◽

Atp Binding Cassette Transporters ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion ◽

Atp Binding Cassette

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Effects of Diets and Drugs on Biliary Cholesterol Secretion in Man

Gallstones ◽

10.1007/978-1-4615-7064-6_17 ◽

1979 ◽

pp. 283-298 ◽

Cited By ~ 3

Author(s):

Scott M. Grundy ◽

H. Y. I. Mok

Keyword(s):

Biliary Cholesterol ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

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Abstract 390: The Absence of Abcg5 Abcg8 Reveals a Sexually Dimorphic Adaption to Impaired Biliary Cholesterol Secretion

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.390 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Jianing Li ◽

Ailing Ji ◽

Ryan E Temel ◽

Deneys R van der Westhuyzen ◽

Gregory A Graf

Keyword(s):

Alternative Pathway ◽

Male Mice ◽

Biliary Cholesterol ◽

Female Mice ◽

Cholesterol Excretion ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion ◽

The Impact ◽

Sterol Excretion ◽

Secretion Rates

Objective: The ABCG5 ABCG8 (G5G8) sterol transporter is the primary mechanism for biliary cholesterol secretion, but mice maintain fecal sterol excretion in its absence. The mechanism by which mice maintain sterol excretion in the absence of this pathway is not known. Transintestinal cholesterol excretion (TICE) is an alternative pathway to hepatobiliary secretion. We investigated the impact of G5G8 deficiency on TICE in the absence of Sitosterolemia. Methods and Results: We compared both hepatobiliary and transintestinal cholesterol excretion rates in wild-type (WT) and G5G8 deficient mice of both sexes. WT and G5G8 were maintained on a plant-sterol free diet from the time of weaning to prevent the development of secondary phenotypes associated with Sitosterolemia. Biliary and intestinal cholesterol secretion rates were determined by biliary diversion with simultaneous perfusion of the proximal 10 cm of the small bowel. Among WT mice, biliary cholesterol secretion was greater in female mice compared to males. Conversely, male mice exhibited greater rates of TICE than females. As expected, WT mice had higher biliary cholesterol secretion rates than their G5G8 deficient littermates. However, the decline in biliary cholesterol secretion was far less in male mice compared to females in the absence of G5G8. In female mice, the absence of G5G8 resulted in a two-fold increase in TICE, whereas males were unaffected. Conclusion: Female mice are more dependent upon the biliary pathway for cholesterol excretion, whereas males are more dependent upon TICE. G5G8 independent pathways are present for both biliary and intestinal cholesterol secretion. Female and male mice differ in their adaptation to G5G8 deficiency in order to maintain fecal sterol excretion.

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Abstract 106: Transintestinal Cholesterol Excretion and Macrophage Reverse Cholesterol Transport are not Stimulated in Hepatic ABCG8 Knockdown Mice Treated with an LXR Agonist

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a106 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Allison L McDaniel ◽

Ryan E Temel ◽

J M Brown ◽

Richard G Lee ◽

Mark J Graham ◽

...

Keyword(s):

Hepatic Cholesterol ◽

Wild Type ◽

Biliary Cholesterol ◽

Neutral Sterol ◽

Atp Binding Cassette Transporter ◽

Cholesterol Excretion ◽

Biliary Cholesterol Secretion ◽

Lxr Agonists ◽

Cholesterol Secretion ◽

Sterol Excretion

Transintestinal cholesterol excretion (TICE) is a recently discovered pathway by which cholesterol travels from plasma to the small intestine for direct excretion into the feces. Hallmarks of animal models with TICE include severely diminished biliary cholesterol secretion but near normal levels of hepatic cholesterol and fecal neutral sterol excretion. Using an ATP binding cassette transporter G8 (ABCG8) antisense oligonucleotide (ASO) to knock down ABCG8 specifically in liver (G8 HKD ), we created a novel mouse model with significantly decreased biliary cholesterol excretion but a 658% increase in hepatic cholesterol accumulation and a 78% reduction in fecal neutral sterol excretion, indicating a dysfunction in the TICE pathway. LXR agonists have previously been shown to stimulate the TICE pathway. In order to more definitively prove the TICE pathway was disfunctional in G8 HKD mice, we treated wild type (WT) and G8 HKD mice with the LXR agonist T0901317 and measured markers of TICE stimulation. As expected, in WT mice, T0901317 doubled biliary cholesterol concentrations. A similar effect was seen in G8 HKD mice treated with T0901317, but biliary cholesterol concentrations remained significantly less than their WT counterparts. These levels of biliary cholesterol closely mirrored hepatic ABCG8 mRNA expression. T0901317 stimulated fecal neutral sterol excretion by >1000% in wild type mice but only by 190% in G8 HKD mice. These data indicate that TICE is disfunctional in G8 HDK mice since the pathway was not stimulated to the same extent in WT and G8 HKD mice by an LXR agonist. Some controversy remains over whether the TICE pathway transports macrophage derived cholesterol. In order to address this issue, we performed a macrophage RCT assay on WT and TICE disfunctional G8 HKD mice. T0901317 stimulated macrophage RCT (fecal neutral sterol 3H dpm) by >2300% in wild type mice but only by 370% in G8 HKD mice. T0901317 increased fecal acidic sterol 3H count by 65-75% in both wild type and G8 HKD mice. These results indicate that macrophage RCT is impaired when the TICE pathway is decreased. In sum, our data shows that hepatic ABCG8 plays a key role in the TICE pathway and that impairing the TICE pathway through hepatic ABCG8 knockdown causes decreased macrophage RCT.

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