A computer study of the risk of cholesterol gallstone associated with obesity and normal weight

AbstractObese people differ from the people of normal weight in gall bladder motility and have a higher risk of cholesterol stone formation. In this study, using a mathematical model of cholesterol homeostasis, which also considers the enterohepatic circulation of bile as well as cholesterol, we investigated the risk of cholesterol stone formation in obese and normal-weight groups who had normal blood cholesterol levels. We associated the risk of stone formation with the amount of cholesterol released into bile and the amount of de novo-synthesized cholic acid. For both groups, we determined the conditions of low and high risk. In addition, we analyzed the potential effects of changes in gall bladder motility with increased weight. The results showed that the obese group exhibited increased kinetics of enterohepatic circulation, leading to a significant increase in blood cholesterol levels, which can be reduced by increasing the amount of cholesterol in bile. Based on this finding, we suggest that for obese people, it is beneficial to reduce the amount and change the composition of circulating bile through the inhibition of cholic acid synthesis along with cholesterol synthesis. Furthermore, obese people should maintain a triglyceride-lowering diet and consume small meals containing fat, preferably in combination with agents that can reduce bile output from the gall bladder.

Download Full-text

The intestinal microbiota regulates host cholesterol homeostasis

BMC Biology ◽

10.1186/s12915-019-0715-8 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 16

Author(s):

Tiphaine Le Roy ◽

Emelyne Lécuyer ◽

Benoit Chassaing ◽

Moez Rhimi ◽

Marie Lhomme ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cholesterol Level ◽

Intestinal Microbiota ◽

Cholesterol Synthesis ◽

Plasma Cholesterol ◽

Cholesterol Homeostasis ◽

Blood Cholesterol ◽

Hepatic Cholesterol ◽

Hepatic Cholesterol Synthesis ◽

Cholesterol Levels

Abstract Background Management of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases. The objective of this study was to investigate how the gut microbiota affects host cholesterol homeostasis at the organism scale. Results We depleted the intestinal microbiota of hypercholesterolemic female Apoe−/− mice using broad-spectrum antibiotics. Measurement of plasma cholesterol levels as well as cholesterol synthesis and fluxes by complementary approaches showed that the intestinal microbiota strongly regulates plasma cholesterol level, hepatic cholesterol synthesis, and enterohepatic circulation. Moreover, transplant of the microbiota from humans harboring elevated plasma cholesterol levels to recipient mice induced a phenotype of high plasma cholesterol levels in association with a low hepatic cholesterol synthesis and high intestinal absorption pattern. Recipient mice phenotypes correlated with several specific bacterial phylotypes affiliated to Betaproteobacteria, Alistipes, Bacteroides, and Barnesiella taxa. Conclusions These results indicate that the intestinal microbiota determines the circulating cholesterol level and may thus represent a novel therapeutic target in the management of dyslipidemia and cardiovascular diseases.

Download Full-text

Two-compartment model as a teaching tool for cholesterol homeostasis

AJP Advances in Physiology Education ◽

10.1152/advan.00141.2014 ◽

2015 ◽

Vol 39 (4) ◽

pp. 372-377 ◽

Cited By ~ 2

Author(s):

Artur Wrona ◽

Joanna Balbus ◽

Olga Hrydziuszko ◽

Krystian Kubica

Keyword(s):

Targeted Delivery ◽

De Novo ◽

Circulatory System ◽

Compartment Model ◽

Cholesterol Homeostasis ◽

Blood Cholesterol ◽

Teaching Tool ◽

Cholesterol Levels ◽

Two Compartment Model ◽

Hands On

Cholesterol is a vital structural and functional molecule in the human body that is only slightly soluble in water and therefore does not easily travels by itself in the bloodstream. To enable cholesterol's targeted delivery to cells and tissues, it is encapsulated by different fractions of lipoproteins, complex particles containing both proteins and lipids. Maintaining cholesterol homeostasis is a highly regulated process with multiple factors acting at both molecular and tissue levels. Furthermore, to regulate the circulatory transport of cholesterol in lipoproteins, the amount of cholesterol present depends on and is controlled by cholesterol dietary intake, de novo synthesis, usage, and excretion; abnormal and/or unbalanced cholesterol levels have been shown to lead to severe outcomes, e.g., cardiovascular diseases. To investigate cholesterol transport in the circulatory system, we have previously developed a two-compartment mathematical model. Here, we show how this model can be used as a teaching tool for cholesterol homeostasis. Using the model and a hands-on approach, students can familiarize themselves with the basic components and mechanisms behind balanced cholesterol circulatory transport as well as investigate the consequences of and countermeasures to abnormal cholesterol levels. Among others, various treatments of high blood cholesterol levels can be simulated, e.g., with commonly prescribed de novo cholesterol synthesis inhibitors.

Download Full-text

Positive Associations Primacy in the IAT

Experimental Psychology (formerly Zeitschrift für Experimentelle Psychologie) ◽

10.1027/1618-3169/a000106 ◽

2011 ◽

Vol 58 (5) ◽

pp. 376-384 ◽

Cited By ~ 10

Author(s):

Pasquale Anselmi ◽

Michelangelo Vianello ◽

Egidio Robusto

Keyword(s):

Implicit Association Test ◽

Rasch Measurement ◽

Normal Weight ◽

Association Test ◽

Primacy Effect ◽

Implicit Association ◽

Obese People ◽

Measurement Analysis ◽

Implicit Prejudice

Two studies investigated the different contribution of positive and negative associations to the size of the Implicit Association Test (IAT) effect. A Many-Facet Rasch Measurement analysis was applied for the purpose. Across different IATs (Race and Weight) and different groups of respondents (White, Normal weight, and Obese people) we observed that positive words increase the IAT effect whereas negative words tend to decrease it. Results suggest that the IAT is influenced by a positive associations primacy effect. As a consequence, we argue that researchers should be careful when interpreting IAT effects as a measure of implicit prejudice.

Download Full-text

Mastication and Energy Expenditure in Normal Weight and Obese People

Case Medical Research ◽

10.31525/ct1-nct04050930 ◽

2019 ◽

Author(s):

Keyword(s):

Energy Expenditure ◽

Normal Weight ◽

Obese People

Download Full-text

Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vijay R. Varma ◽

H. Büşra Lüleci ◽

Anup M. Oommen ◽

Sudhir Varma ◽

Chad T. Blackshear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Tissue ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

Transcriptomic Data ◽

Brain Cholesterol ◽

Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Download Full-text

Dietary raffinose ameliorates hepatic lipid accumulation induced by cholic acid via modulation of enterohepatic bile acid circulation in rats

British Journal Of Nutrition ◽

10.1017/s0007114521002610 ◽

2021 ◽

pp. 1-26

Author(s):

Kenta Maegawa ◽

Haruka Koyama ◽

Satoru Fukiya ◽

Atsushi Yokota ◽

Koichiro Ueda ◽

...

Keyword(s):

Acetic Acid ◽

Bile Acid ◽

Cholic Acid ◽

Lipid Accumulation ◽

Enterohepatic Circulation ◽

Control Diet ◽

Hepatic Triglyceride ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Abstract Enterohepatic circulation of 12α-hydroxylated (12αOH) bile acid (BA) is enhanced depending on the energy intake in high-fat diet-fed rats. Such BA metabolism can be reproduced using a diet supplemented with cholic acid (CA), which also induces simple steatosis, without inflammation and fibrosis, accompanied by some other symptoms that are frequently observed in the condition of non-alcoholic fatty liver in rats. We investigated whether supplementation of the diet with raffinose (Raf) improves hepatic lipid accumulation induced by the CA-fed condition in rats. After acclimation to the AIN-93-based control diet, male Wistar rats were fed diets supplemented with a combination of Raf (30 g/kg diet) and/or CA (0.5 g/kg diet) for 4 weeks. Dietary Raf normalised hepatic triglyceride levels (two-way ANOVA P<0.001 for CA, P=0.02 for Raf, and P=0.004 for interaction) in the CA-supplemented diet-fed rats. Dietary Raf supplementation reduced hepatic 12αOH BA concentration (two-way ANOVA P<0.001 for CA, P=0.003 for Raf, and P=0.03 for interaction). The concentration of 12αOH BA was reduced in the aortic and portal plasma. Raf supplementation increased acetic acid concentration in the caecal contents (two-way ANOVA P=0.001 as a main effect). Multiple regression analysis revealed that concentrations of aortic 12αOH BA and caecal acetic acid could serve as predictors of hepatic triglyceride concentration (R2=0.55, P<0.001). However, Raf did not decrease the secondary 12αOH BA concentration in the caecal contents as well as the transaminase activity in the CA diet-fed rats. These results imply that dietary Raf normalises hepatic lipid accumulation via suppression of enterohepatic 12αOH BA circulation.

Download Full-text

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/10742484211023632 ◽

2021 ◽

pp. 107424842110236

Author(s):

Ruihai Zhou ◽

George A. Stouffer ◽

Sidney C. Smith

Keyword(s):

Cardiovascular Disease ◽

Clinical Outcomes ◽

Mechanism Of Action ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Blood Cholesterol ◽

Atherosclerotic Cardiovascular Disease ◽

Pcsk9 Inhibitors ◽

Cholesterol Lowering ◽

Cholesterol Levels

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

Download Full-text

Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

eLife ◽

10.7554/elife.02882 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 131

Author(s):

Akash Das ◽

Michael S Brown ◽

Donald D Anderson ◽

Joseph L Goldstein ◽

Arun Radhakrishnan

Keyword(s):

Plasma Membrane ◽

Regulatory Mechanism ◽

Low Density Lipoprotein ◽

Human Fibroblasts ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Mutant Form ◽

Perfringolysin O ◽

Cholesterol Levels ◽

Plasma Membrane Cholesterol

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

Download Full-text