scholarly journals Regulation of biliary cholesterol secretion in the rat. Role of hepatic cholesterol esterification.

1984 ◽  
Vol 74 (6) ◽  
pp. 2226-2237 ◽  
Author(s):  
F Nervi ◽  
M Bronfman ◽  
W Allalón ◽  
E Depiereux ◽  
R Del Pozo
Keyword(s):  
Cholesterol Esterification ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion

Relationship between Hepatic Cholesterol Synthesis and Biliary Cholesterol Secretion in Man: Hepatic Cholesterol Synthesis is not a Major Regulator of Biliary Lipid Secretion

1982 ◽  
Vol 62 (5) ◽  
pp. 515-519 ◽  
Author(s):  
P. N. Maton ◽  
A. Reuben ◽  
R. H. Dowling
Keyword(s):  
Bile Acid ◽  
Cholesterol Synthesis ◽  
Acid Output ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Lipid Secretion ◽  
Hepatic Cholesterol Synthesis ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion

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.

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

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.

Impaired biliary lipid secretion in obese Zucker rats: leptin promotes hepatic cholesterol clearance

2001 ◽  
Vol 281 (2) ◽  
pp. G393-G404 ◽  
Author(s):  
Sonya VanPatten ◽  
Narasimha Ranginani ◽  
Sarah Shefer ◽  
Lien B. Nguyen ◽  
Luciano Rossetti ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Plasma Cholesterol ◽  
Zucker Rats ◽  
High Dose ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Obese Rats ◽  
Biliary Cholesterol Secretion ◽  
Plasma Leptin ◽  
Cholesterol Secretion

Human obesity is associated with elevated plasma leptin levels. Obesity is also an important risk factor for cholesterol gallstones, which form as a result of cholesterol hypersecretion into bile. Because leptin levels are correlated with gallstone prevalence, we explored the effects of acute leptin administration on biliary cholesterol secretion using lean ( FA/−) and obese ( fa/fa) Zucker rats. Zucker ( fa/fa) rats become obese and hyperleptinemic due to homozygosity for a missense mutation in the leptin receptor, which diminishes but does not completely eliminate responsiveness to leptin. Rats were infused intravenously for 12 h with saline or pharmacological doses of recombinant murine leptin (5 μg · kg−1 · min−1) sufficient to elevate plasma leptin concentrations to 500 ng/ml compared with basal levels of 3 and 70 ng/ml in lean and obese rats, respectively. Obesity was associated with a marked impairment in biliary cholesterol secretion. In biles of obese compared with lean rats, bile salt hydrophobicity was decreased whereas phosphatidylcholine hydrophobicity was increased. High-dose leptin partially normalized cholesterol secretion in obese rats without altering lipid compositions, implying that both chronic effects of obesity and relative resistance to leptin contributed to impaired biliary cholesterol elimination. In lean rats, acute leptin administration increased biliary cholesterol secretion rates. Without affecting hepatic cholesterol contents, leptin downregulated hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, upregulated activities of both sterol 27-hydroxylase and cholesterol 7α-hydroxylase, and lowered plasma very low-density lipoprotein cholesterol concentrations. Increased biliary cholesterol secretion in the setting of decreased cholesterol biosynthesis and increased catabolism to bile salts suggests that leptin promotes elimination of plasma cholesterol.

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