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.

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

1985 ◽  
Vol 69 (1) ◽  
pp. 71-79 ◽  
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.

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.

scholarly journals Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats

1990 ◽  
Vol 64 (1) ◽  
pp. 161-169 ◽  
Author(s):  
Satoshi Nagaoka ◽  
Hitoshi Miyazaki ◽  
Yoritaka Aoyama ◽  
Akira Yoshida
Keyword(s):  
Polychlorinated Biphenyls ◽  
Bile Acids ◽  
Cholesterol Synthesis ◽  
Control Group ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Faecal Excretion ◽  
Hepatic Cholesterol Synthesis ◽  
Total Bile Acids

Dietary polychlorinated biphenyls (PCBs) caused hypercholesterolaemia in rats. The concentration and output of biliary cholesterol was significantly lower than that of the control group. Biliary output of total bile acids was significantly decreased in rats given the PCB-supplemented diet. Faecal excretion of total steroids (sum of neutral steroids and acidic steroids) was not significantly changed in rats given the PCB-supplemented diet. The present results indicate that dietary PCBs cause hypercholesterolaemia without modifying the faecal total steroids excretion. These results suggest that PCBs produce hyper-cholesterolaemia accompanied by changes in biliary or faecal excretion of bile acids and neutral steroids in addition to an increase in hepatic cholesterol synthesis.

54Role of the gut microbiome for the cholesterol lowering effect of atorvastatin

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F Zimmermann ◽  
D Schmidt ◽  
U Escher ◽  
A Jasina ◽  
J Roessler ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Cholesterol Synthesis ◽  
Interindividual Variation ◽  
Hepatic Cholesterol ◽  
Atorvastatin Treatment ◽  
Hepatic Cholesterol Synthesis ◽  
Lowering Effect ◽  
Expression Of Genes ◽  
Gnotobiotic Mice

Abstract Background and aims Statins show interindividual differences in the extent of low-density lipoprotein cholesterol (LDL-C) reduction. The mechanisms of this interindividual variation are not fully understood. Here, we examined the potential role of the gut microbiome for the LDL-C lowering property of atorvastatin. Methods Mice (C57BL/6) with either intact (conventional mice, CONV, n=24) or with antiobiotic depleted gut microbiome (gnotobiotic, n=16), were put on standard chow diet (SCD) (n=11) or high fat diet (HFD) (n=29) for 6 weeks. During the last 4 weeks atorvastatin (Ator, 10mg/kg body weight/day) or control vehicle was orally applied via gavage. Blood levels of LDL-C and glucose and body weight after 6 weeks of treatment were compared between the groups. Expression of genes involved in hepatic and intestinal cholesterol-metabolism were examined. Faeces of CONV mice were analyzed for alteration of the gut microbiota profile upon atorvastatin treatment using 16S rRNA qPCR. Results HFD fed mice with intact gut microbiome showed significantly increased blood LDL-C levels as compared to SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P<0.01). Bodyweight gain or blood glucose levels after HFD were not significantly different between CONV and gnotobiotic mice. While in CONV mice atorvastatin significantly reduced LDL-C levels after HFD, in gnotobiotic mice the LDL-C lowering effect of atorvastatin was attenuated (CONV+HFD+Ator: 31.0±1.8 mg/dl vs. gnotobiotic mice+HFD+Ator: 46.4±3 mg/dl; P<0.01). The expression of genes involved in hepatic cholesterol synthesis was not significantly altered in gnotobiotic mice as compared to CONV mice. In CONV mice HFD decreased the relative abundance of the bacterial phyla Bacteroidetes and increased the abundance of Firmicutes as compared to SCD. The ratio between Firmicutes to Bacteroidetes was shifted towards control conditions upon atorvastatin treatment. Conclusions The results of this study suggest a regulatory impact of atorvastatin on the gut-microbial profile and, in turn, a crucial role of the gut-microbiome for the LDL-C lowering effect of atorvastatin independent of its regulation of hepatic cholesterol synthesis. Our findings provide novel insight into potential microbiota-related mechanisms causing interindividual variation in LDL-C lowering effects of statins. Acknowledgement/Funding German Heart Research Foundation

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