The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination

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.

Download Full-text

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.

Download Full-text

Multiple mechanisms limit the accumulation of unesterified cholesterol in the small intestine of mice deficient in both ACAT2 and ABCA1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00190.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. G1012-G1022 ◽

Cited By ~ 25

Author(s):

Stephen D. Turley ◽

Mark A. Valasek ◽

Joyce J. Repa ◽

John M. Dietschy

Keyword(s):

Small Intestine ◽

Mrna Level ◽

Cholesterol Absorption ◽

Cholesterol Homeostasis ◽

High Cholesterol Diet ◽

Unesterified Cholesterol ◽

Compensatory Mechanisms ◽

Niemann Pick ◽

Sterol Excretion ◽

Deficient Mice

Cholesterol homeostasis in the enterocyte is regulated by the interplay of multiple genes that ultimately determines the net amount of cholesterol reaching the circulation from the small intestine. The effect of deleting these genes, particularly acyl CoA:cholesterol acyl transferase 2 (ACAT2), on cholesterol absorption and fecal sterol excretion is well documented. We also know that the intestinal mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1) increases in Acat2−/− mice. However, none of these studies has specifically addressed how ACAT2 deficiency impacts the relative proportions of esterified and unesterified cholesterol (UC) in the enterocyte and whether the concurrent loss of ABCA1 might result in a marked buildup of UC. Therefore, the present studies measured the expression of numerous genes and related metabolic parameters in the intestine and liver of ACAT2-deficient mice fed diets containing either added cholesterol or ezetimibe, a selective sterol absorption inhibitor. Cholesterol feeding raised the concentration of UC in the small intestine, and this was accompanied by a significant reduction in the relative mRNA level for Niemann-Pick C1-like 1 (NPC1L1) and an increase in the mRNA level for both ABCA1 and ABCG5/8. All these changes were reversed by ezetimibe. When mice deficient in both ACAT2 and ABCA1 were fed a high-cholesterol diet, the increase in intestinal UC levels was no greater than it was in mice lacking only ACAT2. This resulted from a combination of compensatory mechanisms including diminished NPC1L1-mediated cholesterol uptake, increased cholesterol efflux via ABCG5/8, and possibly rapid cell turnover.

Download Full-text

Reduced fecal sterol excretion in subjects with familial hypoalphalipoproteinemia

Atherosclerosis ◽

10.1016/j.atherosclerosis.2009.06.022 ◽

2009 ◽

Vol 207 (2) ◽

pp. 614-616 ◽

Cited By ~ 11

Author(s):

Karim El Harchaoui ◽

Remco Franssen ◽

G. Kees Hovingh ◽

Radjesh J. Bisoendial ◽

Frans Stellaard ◽

...

Keyword(s):

Sterol Excretion

Download Full-text

Lowering of Plasma Cholesterol and Enhanced Sterol Excretion with the Consumption of Polyunsaturated Ruminant Fats

New England Journal of Medicine ◽

10.1056/nejm197302222880801 ◽

1973 ◽

Vol 288 (8) ◽

pp. 379-382 ◽

Cited By ~ 83

Author(s):

Paul J. Nestel ◽

Nathalie Havenstein ◽

H. Malcolm Whyte ◽

Trevor J. Scott ◽

Len J. Cook

Keyword(s):

Plasma Cholesterol ◽

Sterol Excretion

Download Full-text

Plasma and Hepatic Cholesterol Levels and Fecal Neutral Sterol Excretion Are Altered in Hamsters Fed Straw Mushroom Diets

Journal of Nutrition ◽

10.1093/jn/128.9.1512 ◽

1998 ◽

Vol 128 (9) ◽

pp. 1512-1516 ◽

Cited By ~ 42

Author(s):

Peter C. K. Cheung

Keyword(s):

Hepatic Cholesterol ◽

Neutral Sterol ◽

Cholesterol Levels ◽

Straw Mushroom ◽

Sterol Excretion

Download Full-text