Biliary lipid composition and gallstone formation in rabbits fed on soy protein, cholesterol, casein and modified casein.
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ABSTRACT:
SUBMITTER: Ozben T
PROVIDER: S-EPMC1133423 | biostudies-other | 1989 Oct
REPOSITORIES: biostudies-other
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Project description:Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.
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Project description:Biliary lipids are a family of four dissimilar molecular species consisting of a mixture of bile salts (substituted cholanoic acids), phospholipids, mostly (>96%) diacylphosphatidylcholines, unesterified cholesterol, and bilirubin conjugates known trivially as lipopigments. The primary pathophysiological defect in cholesterol gallstone disease is hypersecretion of hepatic cholesterol into bile with less frequent hyposecretion of bile salts and/or phospholipids. Several other gallbladder abnormalities contribute and include hypomotility, immune-mediated inflammation, hypersecretion of gelling mucins, and accelerated phase transitions; there is also reduced intestinal motility that augments "secondary" bile salt synthesis by the anaerobic microflora. Cholesterol nucleation is initiated when unilamellar vesicles of cholesterol plus biliary phospholipids fuse to form multilamellar vesicles. From these "plate-like" cholesterol monohydrate crystals, the building blocks of macroscopic stones are nucleated heterogeneously by mucin gel. Multiple Lith gene loci have been identified in inbred mice, paving the way for discovery of an ever-increasing number of LITH genes in humans. Because of the frequency of the metabolic syndrome today, insulin resistance and LITH genes all interact with a number of environmental cholelithogenic factors to cause the gallstone phenotype. This review summarizes current concepts of the physical-chemical state of biliary lipids in health and in lithogenic bile and outlines the molecular, genetic, hepatic, and cholecystic factors that underlie the pathogenesis of cholesterol gallstones.
| S-EPMC2674701 | biostudies-literature
Project description:Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).
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Project description:Rabbits are a suitable animal model for atherosclerosis due to their sensitivity to dietary cholesterol. Moreover, rabbits have lipoprotein profiles that are more similar to humans than those of other laboratory animals. However, little is known about the transcriptomic information related to atherosclerosis in rabbits. We aimed to determine the changes in the livers of rabbits fed a normal chow diet (control) or high cholesterol diet (HCD) by histological examinations and RNA sequencing analysis. Compared with the control group, the lipid levels and small LDL subfractions in plasma were increased, and aortic atherosclerotic plaques were formed in the HCD group. Most importantly, HCD resulted in lipid accumulation and inflammation in the livers. Transcriptomic analysis of the liver showed that HCD induces 1183 differentially expressed genes (DEGs) that mainly participate in the regulation of inflammation and lipid metabolism. Furthermore, the signaling pathways involved in inflammation and lipid metabolism were enriched by KEGG pathway analysis. In addition, hepatic DEGs of the HCD group were further validated by real-time PCR. These results suggest that HCD causes liver lipid accumulation and inflammatory response. Although the relationships between these hepatic changes and atherogenesis need further investigation, these findings provide a fundamental framework for future research on human atherosclerosis using rabbit models.
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Project description:BackgroundThe protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and biliary secretion. Mechanistically, the purinergic P2Y13 ADP-receptor is involved in hepatic HDL endocytosis (i.e., uptake of both HDL protein + lipid moieties), which is considered an important step of RCT. Accordingly, chow-fed P2Y13 knockout (P2Y13-/-) mice exhibit lower hepatic HDL uptake, which translates into a decrease of hepatic free cholesterol content and biliary cholesterol and phospholipid secretion.FindingsThe aim of this study was to determine the effect of high cholesterol diet (HCD) in P2Y13-/- mice, in order to mimic high dietary cholesterol intake, which is a major cause of dyslipidemia in humans. As previously reported with chow-diet, HCD did not affect plasma lipid levels in P2Y13-/- compared with control mice but decreased hepatic free and esterified cholesterol content (p < 0.05, P2Y13-/- versus control). Interestingly, biliary lipid secretion and macrophages-to-feces RCT were more dramatically impaired in P2Y13-/- mice fed a HCD than chow-diet. HCD did not enhance atherosclerosis in P2Y13-/- compared with control mice.ConclusionThis study demonstrates that high dietary cholesterol intake accentuated the metabolic phenotype of P2Y13-/- mice, with impaired hepatobiliary RCT. Although other animal models might be required to further evaluate the role of P2Y13 receptor in atherosclerosis, P2Y13 appears a promising target for therapeutic intervention aiming to stimulate RCT, particularly in individuals with lipid-rich diet.
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Project description:Consumption of dietary protein at recommended levels is considered a potential strategy to promote satiety and weight management, but how protein from different dietary sources effect the obesity development, lipid metabolism, and gut microbiota is not known. This study focused on the effects of beef, casein, and soy protein diet on lipid metabolism, triglycerides accumulation, and microbial diversity in colon of C57BL/6J mice, which were given either low-fat diets (LFD, 12% Kcal) or high-fat diets (HFD, 60% Kcal) for 12 weeks. Body and liver weight increased significantly in mice fed a beef protein HFD (HFB), whereas reduced cumulative energy intake was seen in a soy protein HFD (HFS) group. HFB-fed mice showed signs of impaired glucose metabolism and insulin resistance along with a significant elevation in the concentration of triglycerides, LDL-cholesterol, total cholesterol, IL1β, TNF-α, IL-6, and leptin in serum. HFB also enhanced lipid accumulation in liver with increased activity of genes important for lipogenesis and hepatic cholesterol metabolism. A 16S rRNA gene sequencing indicated that HFD, regardless of proteins, significantly enhanced the ratio of Firmicutes to Bacteroidetes in colonic microbiota. However, HFB not only reduced the abundance of Akkermansia, compared with LFD independent of proteins, but also decreased the abundance of butyrate-producing bacteria such as Anaerotruncus, Butyricicoccus, and Lactobacillus (P < 0.05) compared with HFS and HFC. In conclusion, consumption of HFB does not only affect the gut microbiota composition but also increases the problems related to metabolic syndromes like dyslipidemia, hypercholesterolemia, and triglycerides accumulation in liver, which lead to systemic inflammation and its associated comorbidities, for example, impaired glucose metabolism and insulin resistance.
| S-EPMC6165900 | biostudies-literature
Project description:Urotensin II (UII) is a vasoactive peptide composed of 11 amino acids that has been implicated to contribute to the development of cardiovascular disease. The purpose of this study was to investigate whether UII affects the development of atherosclerosis in cholesterol-fed rabbits. UII was infused for 16 weeks through an osmotic mini-pump into male Japanese White rabbits fed on a high-cholesterol diet. Plasma lipids and body weight were measured every 4 weeks. Aortic atherosclerotic lesions along with cellular components, collagen fibers, matrix metalloproteinase-1 and -9 were examined. Moreover, vulnerability index of atherosclerotic plaques was evaluated. UII infusion significantly increased atherosclerotic lesions within the entire aorta by 21% over the control (P?=?0.013). Atherosclerotic lesions were increased by 24% in the aortic arch (P?=?0.005), 11% in the thoracic aorta (P?=?0.054) and 18% in the abdominal aorta (P?=?0.035). These increases occurred without changes in plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or body weight. Immunohistochemical staining revealed that macrophages and matrix metalloproteinase-9 were significantly enhanced by 2.2-fold and 1.6-fold in UII group. In vitro studies demonstrated that UII up-regulated the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells, which was inhibited by the UII receptor antagonist urantide. In conclusion, our results showed that UII promotes the development of atherosclerotic lesions and destabilizes atherosclerotic plaques in cholesterol-fed rabbits.
| S-EPMC3991611 | biostudies-other
Project description:Here we undertook a proteomic investigation of ascending aorta from New Zealand White rabbits after 10 weeks on a high (2% w/w) cholesterol diet (HCD, n=5) or control diet (n=5) in order to profile the proteomic changes in response to the HCD. Histology confirmed intimal thickening in the HCD group and LC-MS/MS analysis of individually obtained ascending aorta extracts labelled with isobaric (iTRAQ) tags led to identification and quantitation of 453 unique proteins above the 1% false discovery rate threshold. Of 67 proteins showing significant differences in relative abundance (p<0.05), 62 were elevated and five decreased in ascending aorta from HCD-fed rabbits compared to controls. Six proteins were selected for validation using Multiple Reaction Monitoring which confirmed the iTRAQ results.
2018-06-21 | PXD002345 | Pride
Project description:BackgroundThe globally rising obesity epidemic is associated with a broad spectrum of diseases including atherosclerosis and non-alcoholic fatty liver (NAFL) disease. In the past, research focused on the vasculature or liver, but chronic systemic effects and inter-organ communication may promote the development of NAFL. Here, we investigated the impact of confined vascular endothelial injury, which produces highly inflamed aortic plaques that are susceptible to rupture, on the progression of NAFL in cholesterol fed rabbits.MethodsAortic atherosclerotic inflammation (plaque Gd-enhancement), plaque size (vessel wall area), and composition, were measured with in vivo magnetic resonance imaging (MRI) in rabbits fed normal chow or a 1% cholesterol-enriched atherogenic diet. Liver fat was quantified with magnetic resonance spectroscopy (MRS) over 3 months. Blood biomarkers were monitored in the animals, with follow-up by histology.ResultsCholesterol-fed rabbits with and without injury developed hypercholesterolemia, NAFL, and atherosclerotic plaques in the aorta. Compared with rabbits fed cholesterol diet alone, rabbits with injury and cholesterol diets exhibited larger, and more highly inflamed plaques by MRI (P?<?0.05) and aggravated liver steatosis by MRS (P?<?0.05). Moreover, after sacrifice, damaged (ballooning) hepatocytes and extensive liver fibrosis were observed by histology. Elevated plasma gamma-glutamyl transferase (GGT; P?=?0.014) and the ratio of liver enzymes aspartate and alanine aminotransferases (AST/ALT; P?=?0.033) indicated the progression of steatosis to non-alcoholic steatohepatitis (NASH).ConclusionsLocalized regions of highly inflamed aortic atherosclerotic plaques in cholesterol-fed rabbits may contribute to progression of fatty liver disease to NASH with fibrosis.
| S-EPMC6071403 | biostudies-literature
Project description:In inbred mice, susceptibility to cholesterol gallstone disease is conferred by Lith genes, which in part promote hypersecretion of cholesterol into bile in response to a high-fat/cholesterol/cholic acid (lithogenic) diet. Because cytosolic sterol carrier protein 2 (SCP2) is believed to participate in cellular cholesterol trafficking and is elevated in the liver cytosol of cholesterol gallstone patients, we defined the hepatic expression of SCP2 during cholesterol gallstone formation in gallstone-susceptible C57L and gallstone-resistant AKR mice fed the lithogenic diet. Steady-state cytosolic SCP2 levels in C57L, but not AKR mice increased as a function of time and were correlated positively with biliary cholesterol hypersecretion, cholesterol saturation indices of gall-bladder biles and the appearance of liquid and solid cholesterol crystals leading to gallstone formation. Steady-state mRNA levels increased co-ordinately, consistent with regulation of SCP2 expression at the transcriptional level. Our results suggest that overexpression of SCP2 contributes to biliary cholesterol hypersecretion and the pathogenesis of gallstones in genetically susceptible mice. Because of the different chromosomal localizations of the Lith and Scp2 genes, we postulate that Lith genes control SCP2 expression indirectly.
| S-EPMC1219838 | biostudies-other