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

1. To examine the role of newly synthesized cholesterol as a determinant of bile lipid secretion, both hepatic cholesterol synthesis (as judged by the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, EC 1.1.1.34; HMGCoAR) and steady state biliary cholesterol output were measured in nine patients. 2. HMGCoAR levels varied four fold (9–40 pmol min−1 mg−1) and biliary cholesterol secretion 2–5-fold (0.60−1.15 μUmol h−1 kg−1) but there was no correlation between these two variables (r = 0.18; P>0.05) nor between biliary bile acid output and HMGCoAR activity (r = 0.34; P>0.05). 3. There was, however, a linear relationship between bile acid and phospholipid secretion (r = 0.77; P<0.001) and between bile acid and cholesterol secretion (r = 0.69; P<0.05). 4. These results suggest that HMGCoAR activity is not a major determinant of cholesterol secretion nor at these secretion rates is HMGCoAR activity related to bile acid return to the liver.

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Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)41977-7 ◽

1991 ◽

Vol 32 (7) ◽

pp. 1143-1149

Author(s):

JC Mitchell ◽

BG Stone ◽

GM Logan ◽

WC Duane

Keyword(s):

Bile Acid ◽

Cholesterol Synthesis ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Biliary Cholesterol ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

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Bile Lipid Secretion in Obese and Non-Obese Individuals with and without Gallstones

Clinical Science ◽

10.1042/cs0690071 ◽

1985 ◽

Vol 69 (1) ◽

pp. 71-79 ◽

Cited By ~ 45

Author(s):

A. Reuben ◽

P. N. Maton ◽

G. M. Murphy ◽

R. H. Dowling

Keyword(s):

Bile Acid ◽

Acid Secretion ◽

Biliary Lipid ◽

Biliary Cholesterol ◽

Cholesterol Gallstones ◽

Lipid Secretion ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion ◽

Bile Acid Secretion ◽

Secretion Rates

1. Biliary lipid secretion rates were measured in non-obese and obese individuals with and without cholesterol gallstones, using a steady-state, amino acid duodenal perfusion method. In addition, biliary lipid secretion rates were measured in five obese gallstone patients receiving high-dose chenodeoxycholic acid therapy (16-22 mg day−1 kg−1). 2. Bile acid secretion rates in the non-obese patients with cholesterol gallstones (563+sem 70 μmol/h, n = 6) were significantly lower than in the non-obese controls (1078 + 210 μmol/h, n = 10, P < 0.05), whereas cholesterol secretion rates were similar in the non-obese individuals with and without gallstones (51+7 and 42+4 μmol/h respectively). 3. In the obese, both with and without gallstones, the major abnormality was hypersecretion of cholesterol (107+7 μmol/h, n = 7, and 81 + 15 μmol/h, n = 7, respectively). Both these values were significantly greater than those in the non-obese controls (P < 0.01-0.02). 4. Biliary cholesterol secretion rates correlated significantly with bile acid secretion rates but, for every mole of bile acid secreted, the obese secreted more cholesterol than the non-obese. 5. Chenodeoxycholic acid treatment lowered biliary cholesterol saturation in obese gallstone patients by reducing biliary cholesterol secretion. 6. These results suggest that there are two major types of defect in biliary lipid secretion in gallstone patients: reduced biliary bile acid secretion in non-obese gallstone patients and excessive biliary cholesterol secretion in the obese.

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ABCG5/ABCG8-independent biliary cholesterol excretion in lactating rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00502.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. G228-G235 ◽

Cited By ~ 7

Author(s):

Donna J. Coy ◽

Clavia R. Wooton-Kee ◽

Baoxiang Yan ◽

Nadezhda Sabeva ◽

Kai Su ◽

...

Keyword(s):

Bile Acid ◽

Mrna Expression ◽

Bile Acids ◽

Sprague Dawley ◽

Biliary Cholesterol ◽

Bile Acid Concentration ◽

Protein Levels ◽

Biliary Cholesterol Secretion ◽

Rats And Mice ◽

Cholesterol Secretion

Lactation is associated with increased expression of bile acid transporters and an increased size and hydrophobicity of the bile acid pool in rats. ATP-binding cassette (ABC) transporters multidrug resistance protein 2 (Mdr2), Abcb11 [bile salt export pump (Bsep)], and Abcg5/Abcg8 heterodimers are essential for the biliary secretion of phospholipids, bile acids, and cholesterol, respectively. We investigated the expression of these transporters and secretion of their substrates in female control and lactating Sprague Dawley rats and C57BL/6 mice. Expression of Abcg5/Abcg8 mRNA was decreased by 97 and 60% by midlactation in rats and mice, respectively; protein levels of Abcg8 were below detection limits in lactating rats. Mdr2 mRNA expression was decreased in lactating rats and mice by 47 and 59%, respectively. Despite these changes in transporter expression, basal concentrations of cholesterol and phospholipid in bile were unchanged in rats and mice, whereas increased Bsep mRNA expression in early lactation coincided with an increased basal biliary bile acid concentration in lactating mice. Following taurocholate infusion, coupling of phospholipid and taurocholate secretion in bile of lactating mice was significantly impaired relative to control mice, with no significant changes in maximal secretion of cholesterol or bile acids. In rats, taurocholate infusion revealed a significantly impaired coupling of cholesterol to taurocholate secretion in bile in lactating vs. control animals. These data reveal marked utilization of an Abcg5/Abcg8-independent mechanism for basal biliary cholesterol secretion in rats during lactation, but a dependence on Abcg5/g8 for maximal biliary cholesterol secretion.

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Abstract 629: FGF15/19 Upregulates Hepatic ABCG5 and ABCG8 to Promote Biliary Cholesterol Secretion

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.629 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Sonja Pijut ◽

Yuhuan Wang ◽

Lisa Bennett ◽

Richard Lee ◽

Gregory Graf

Keyword(s):

Body Weight ◽

Bile Acid ◽

Protein Expression ◽

Cholesterol Metabolism ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Wild Type ◽

Biliary Cholesterol ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

Background: Elevated hepatic cholesterol is thought to contribute to the development of nonalcoholic fatty liver disease, a condition highly associated with cardiovascular risk factors. The ABCG5 and ABCG8 (G5G8) heterodimer is responsible for up to 90% of biliary cholesterol secretion and is a potential therapeutic target for promoting cholesterol elimination. We have previously demonstrated that ursodiol (UDCA), a pharmacologic bile acid, increases G5G8 protein expression and biliary cholesterol secretion. However, whole body cholesterol elimination is minimized likely due to simultaneous suppression of bile acid synthesis through upregulation of FGF15/19. The objectives of this study are to determine whether FGF15/19 regulates G5G8 and determine whether UDCA requires FGF15/19 signaling in order to upregulate G5G8. Methods: Mice were injected with two doses of FGF19 or carrier (PBS) 1μg/g body weight within an 8-hour treatment window. A separate group of wild type (WT) and G5G8 knockout (KO) mice were similarly injected with FGF19. In another experiment, WT mice were fed chow or UDCA-supplemented diet in the absence or presence of FGF15/19 signaling inhibition which was achieved by FGFR4 antisense oligonucleotide (ASO) supplied by Ionis Pharmaceuticals. In all experiments, body weight, liver weight, bile flow rate and plasma, hepatic and biliary lipids were measured. Immunoblotting of G5G8 and real-time PCR of genes involved in cholesterol metabolism were also conducted. Results: Mice injected with FGF19 had increased biliary lipids (PBS: 5.287±0.5720, FGF19: 8.098±0.6114, n=6), decreased Cyp7a1 (PBS: 1.021±0.1064 FGF19: 0.07787±0.01345 n=5-7) and Cyp8b1 (PBS: 1.018±0.09846, FGF19: 0.2647±0.05609, n=5-7) expression, and increased G5G8 protein expression compared to mice injected with PBS. In G5G8 KO mice injected with FGF19, there was only a small increase in plasma free cholesterol (WT: 51.96±2.098, KO: 62.24±2.562, n=4) and no other significant changes in cholesterol metabolism compared to wild type mice injected with FGF19. Conclusion: In conclusion, FGF15/19 suppresses bile acid synthesis and post-transcriptionally upregulates G5G8. However, in the absence of G5G8, FGF15/19 did not disrupt cholesterol metabolism.

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Minor role of de novo cholesterol synthesis in biliary cholesterol secretion: Studies in healthy humans

Hepatology ◽

10.1016/0270-9139(95)95663-8 ◽

1995 ◽

Vol 22 (4) ◽

pp. A485

Author(s):

J SCHEIBNER

Keyword(s):

Cholesterol Synthesis ◽

De Novo ◽

Minor Role ◽

Biliary Cholesterol ◽

Healthy Humans ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion

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Simultaneous Determination of Biliary and Intestinal Cholesterol Secretion Reveals That CETP (Cholesteryl Ester Transfer Protein) Alters Elimination Route in Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.312952 ◽

2019 ◽

Vol 39 (10) ◽

pp. 1986-1995 ◽

Cited By ~ 3

Author(s):

Jianing Li ◽

Sonja S. Pijut ◽

Yuhuan Wang ◽

Ailing Ji ◽

Rupinder Kaur ◽

...

Keyword(s):

Bile Acid ◽

Cholesteryl Ester ◽

Cholesteryl Ester Transfer Protein ◽

Density Lipoprotein ◽

High Fat ◽

Biliary Cholesterol ◽

Transfer Protein ◽

Biliary Cholesterol Secretion ◽

Cholesterol Secretion ◽

The Impact

Objective: Determine the impact of CETP (cholesteryl ester transfer protein) on the route of cholesterol elimination in mice. Approach and Results: We adapted our protocol for biliary cholesterol secretion with published methods for measuring transintestinal cholesterol elimination. Bile was diverted and biliary lipid secretion maintained by infusion of bile acid. The proximal small bowel was perfused with bile acid micelles. In high-fat, high-cholesterol–fed mice, the presence of a CETP transgene increased biliary cholesterol secretion at the expense of transintestinal cholesterol elimination. The increase in biliary cholesterol secretion was not associated with increases in hepatic SR-BI (scavenger receptor BI) or ABCG5 (ATP-binding cassette G5) ABCG8. The decline in intestinal cholesterol secretion was associated with an increase in intestinal Niemann-Pick disease, type C1, gene-like 1 mRNA. Finally, we followed the delivery of HDL (high-density lipoprotein) or LDL (low-density lipoprotein) cholesteryl esters (CE) from plasma to bile and intestinal perfusates. HDL-CE favored the biliary pathway. Following high-fat feeding, the presence of CETP directed HDL-CE away from the bile and towards the intestine. The presence of CETP increased LDL-CE delivery to bile, whereas the appearance of LDL-CE in intestinal perfusate was near the lower limit of detection. Conclusions: Biliary and intestinal cholesterol secretion can be simultaneously measured in mice and used as a model to examine factors that alter cholesterol elimination. Plasma factors, such as CETP, alter the route of cholesterol elimination from the body. Intestinal and biliary cholesterol secretion rates are independent of transhepatic or transintestinal delivery of HDL-CE, whereas LDL-CE was eliminated almost exclusively in the hepatobiliary pathway.

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