scholarly journals Long-term intake of soyabean phytosterols lowers serum TAG and NEFA concentrations, increases bile acid synthesis and protects against fatty liver development in dyslipidaemic hamsters

2014 ◽  
Vol 112 (5) ◽  
pp. 663-673 ◽  
Author(s):  
Sirle Laos ◽  
Antoni Caimari ◽  
Anna Crescenti ◽  
Jamileh Lakkis ◽  
Francesc Puiggròs ◽  
...  
Keyword(s):  
Bile Acid ◽  
Fatty Liver ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Plasma Cholesterol ◽  
Fold Increase ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Cholesterol Ratio

Various human trials and pre-clinical studies have suggested that dietary plant sterols possess hypotriacylglycerolaemic properties apart from their cholesterol-lowering properties. We hypothesised that phytosterols (PS) might attenuate triacylglycerolaemia by interfering with the deleterious effects of cholesterol overload in the liver. In the present study, twenty hamsters (Mesocricetus auratus) with diet-induced combined hyperlipidaemia were fed a high-fat diet (HFD, n 10) or a HFD supplemented with soyabean PS (n 10) for 40 d. In parallel, a healthy group was fed a standard diet (n 10). PS normalised fasting plasma cholesterol concentrations completely after 20 d and were also able to normalise serum TAG and NEFA concentrations after 40 d. HFD feeding caused microvesicular steatosis and impaired the expression of key genes related to fatty acid oxidation such as PPARA, carnitine palmitoyltransferase-Iα (CPT1A) and phosphoenolpyruvate carboxykinase 1 (PCK1) in the liver. PS treatment completely protected against HFD-induced steatosis and resulted in a normalised hepatic gene expression profile. The protection of the hepatic function by PS was paralleled by increased faecal cholesterol excretion along with a 2-fold increase in the biliary bile acid (BA):cholesterol ratio. The present study supports the conclusion that long-term consumption of PS can reduce serum TAG and NEFA concentrations and can protect against the development of fatty liver via different mechanisms, including the enhancement of BA synthesis. The results of the present study place these compounds as promising hepatoprotective agents against fatty liver and its derived pathologies.

scholarly journals Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

2021 ◽  
Author(s):  
Akihiko Kimura ◽  
Tatsuki Mizuochi ◽  
Hajime Takei ◽  
Akira Ohtake ◽  
Jun Mori ◽  
...  
Keyword(s):  
Bile Acid ◽  
Chenodeoxycholic Acid ◽  
Acid Treatment ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

scholarly journals Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

2016 ◽  
Vol 113 (13) ◽  
pp. E1796-E1805 ◽  
Author(s):  
Geraldine Harriman ◽  
Jeremy Greenwood ◽  
Sathesh Bhat ◽  
Xinyi Huang ◽  
Ruiying Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthesis ◽  
Fatty Liver Disease ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

scholarly journals Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

2020 ◽  
Vol 318 (3) ◽  
pp. G554-G573 ◽  
Author(s):  
John Y. L. Chiang ◽  
Jessica M. Ferrell
Keyword(s):  
Bile Acid ◽  
Fatty Liver ◽  
Bile Acids ◽  
G Protein ◽  
Liver Diseases ◽  
Metabolic Diseases ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Receptors ◽  
G Protein Coupled

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

INCREASED FACTOR VII REACTIVITY IN THE RABBIT FOLLOWING DIET-INDUCED HYPERCHOIESTEROIAEMIA

1987 ◽  
Author(s):  
K A Mitropoulos ◽  
S J Walter ◽  
T W Meade ◽  
M P Esnouf
Keyword(s):  
Plasma Cholesterol ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Plasma Lipoproteins ◽  
Cholesterol Concentration ◽  
Factor Vii ◽  
Standard Diet ◽  
Factor X ◽  
Single Chain

The association of factor VII coagulant activity (VIIC) with plasma lipid concentrations has been a consistent feature of a number of studies in man and points to plasma lipoproteins as determinants of VIIC.To modify plasma lipoprotein concentrations and to study the effect of this on VIIC, rabbits were fed a 1%- cholesterol-supplemented diet. Treatment resulted in a many-fold increase in plasma cholesterol concentration with the major fraction of excess cholesterol associated with the very low and intermediate density lipoprotein fractions. VIIC was considerably higher in rabbits fed 1%- cholesterol-supplemented than in rabbits fed the standard diet. In both groups of rabbits, the direction and extent of variation in VIIC coincided with variation in cholesterol concentration so that over time there were significant and positive correlations between VIIC and plasma cholesterol. A method that provides a measure of the total functionalfactor VII concentration (VII) was also used. This assay involves clotting the plasma in the presence of excess tissue factor and therefore the conversion of VII tothe more reactive two-chain form of theprotein (αVIIa) .The concentration of αVIIa present in the serum was measured from the rate of activation of excess of [sialyl-3H]-bovine factor X. By day 10 of treatment, and in all furthercomparisons VTIt was only slightly higher in the group of rabbits fed cholesterol-supplemented than in that fed the standard diet.This increase in VI11 istoo small to explain the considerable increasin VIIC in the hypercholesterolaemic rabbit. We conclude thattheincrease in VIIc was to ahigher proportion of αVIIa in theplasma of hyperchol⋆esterol-aemic rabbits rather thanto an increase in the concentration of the single-chain protein.

Safety and Efficacy of Long-Term Diet and Diet Plus Bile Acid-Binding Resin Cholesterol-Lowering Therapy in 73 Children Heterozygous for Familial Hypercholesterolemia

PEDIATRICS ◽  
1986 ◽  
Vol 78 (2) ◽  
pp. 338-348 ◽  
Author(s):  
Charles J. Glueck ◽  
Margot J. Mellies ◽  
Mark Dine ◽  
Tammy Perry ◽  
Peter Laskarzewski
Keyword(s):  
Bile Acid ◽  
Familial Hypercholesterolemia ◽  
Plasma Cholesterol ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Normal Children ◽  
Cholesterol Lowering ◽  
Bile Acid Binding

Our specific aim was to examine the efficacy and safety of long-term cholesterol-lowering diet and bile acid-binding resin therapy in 73 children heterozygous for familial hypercholesterolemia (FH). We prospectively followed accretion of height and weight in 40 FH children for 5.8 years on diet alone and in 33 FH children for 4.3 years on diet and bile acid-binding resins (8 to 20 g/d). In 67 of these 73 children, sequential data on plasma choleterol lowering was obtained, including 32 children on diet plus bile acid-binding resins and 35 on diet alone. For all 73 children, median age, sex, and race-specific percentiles for height and weight at entry were 50 and 50, respectively, and, 5.7 years later, were unchanged at 50 and 50. Initial and final percentiles for height (r = .76, P < .001) and weight (r = .70, P < .001) were closely correlated. Percentile distributions for height and weight at entry into the study did not differ from those at the end of follow-up (P > .1), in both the 40 FH children on diet alone and the 33 on diet plus bile acid-binding resins. Tracking of height and weight did not differ in the 40 children on diet alone v the 33 on diet plus bile acidbinding resins (P > .1). During 6 years of follow-up there were no significant differences in the percentage of serial, postbaseline measurements for height which were either less than or greater than or equal to baseline percentiles, comparing 40 FH children on diet alone, 33 FH children on diet plus resin, and 39 normal children (on ad libitum diet). FH children on diet or plus resin had a smaller percentage of weight measurements equal to or more than baseline percentiles than normals on follow-up (P < .01), probably reflecting restriction of total fat intake to < 35% of calories. On diet alone, 32 FH children had total plasma cholesterol of 307 ± 8 mg/dL (mean ± SE); bile acidbinding resins were added to diet in these children at an average age of 11.5 years, with this regimen maintained for 4.6 ± 0.4 years, leading to a mean reduction in total plasma cholesterol of 12.5% ± 2% beyond the effects of diet alone (P<.01). On diet plus bile acid-binding resins, 44% of children had a reduction of total plasma cholesterol ≤14%; 28% had a reduction ≥21% (beyond the effects of diet alone.) Thirty-five FH children (starting at 11.7 years of age) were treated with diet alone. Their mean total plasma cholesterol at baseline was 243 ± 6 mg/dl and decreased 9.6% ± 2% (P<.01) after an average of 4.5 ± 0.5 years of diet. On diet alone, 29% of children had a reduction of total plasma cholesterol ≥14%, and 23% had a reduction ≥21%. Long-term diet and bile acid-binding resin therapy did not affect normal growth in 73 FH children and was effective in reducing total plasma cholesterol levels within ranges previously shown to have efficacy in reducing coronary heart disease events in hypercholesterolemic men.

scholarly journals Dietary rhubarb (Rheum rhaponticum) stalk fibre does not lower plasma cholesterol levels in diabetic rats

2003 ◽  
Vol 89 (2) ◽  
pp. 201-206 ◽  
Author(s):  
Sukhinder Kaur Cheema ◽  
Vinti Goel ◽  
Tapan K. Basu ◽  
Luis B. Agellon
Keyword(s):  
Bile Acid ◽  
Binding Capacity ◽  
Plasma Cholesterol ◽  
Cellulose Fibre ◽  
Acid Synthesis ◽  
Diabetic Rats ◽  
Mrna Abundance ◽  
Diabetic Rat ◽  
Mrna Levels ◽  
Experimental Conditions

Rhubarb (Rheum rhapontiam) stalk fibre was previously shown to be hypolipidaemic under clinical and experimental conditions. The present study was undertaken to investigate whether rhubarb stalk fibre has a hypolipidaemic effect under diabetic conditions. Two models of diabetic rats were used: streptozotocin-induced diabetic rats, and diabetes-prone BB (BBdp) rats. The plasma cholesterol and triacylglycerol concentrations were elevated after the onset of diabetes in BBdp rats, but not in sterptozotocin-induced diabetic rats. The rhubarb-fibre diet had no effect on the plasma cholesterol or triacylglycerol concentrations of diabetic rats. The hypolipidaemic effect of rhubarb stalk fibre has been suggested to be due to the bile-acid-binding capacity of rhubarb fibre, which in turn up regulates cholesterol 7α-hydroxylase (cyp7a) activity. cyp7a is the first and the rate-limiting enzyme in the breakdown of cholesterol to bile acids. We measured the cyp7a activity and mRNA levels in control and diabetic rats fed rhubarb- and cellulose-fibre diets. The cyp7a activity and mRNA abundance were increased in both diabetic rat models, indicating that bile acid synthesis is enhanced in diabetes. Feeding a diet enriched with rhubarb fibre caused a slight but significant increase (P<0·05) in cyp7a enzyme activity in BBdp rats, but no change in cyp7a mRNA abundance was detected. These results suggest that although a rhubarb-fibre-enriched diet increased cyp7a activity in BBdp rats, there was no apparent therapeutic benefit in terms of lowering plasma cholesterol concentrations.

scholarly journals Effects of long-term plant sterol or stanol ester consumption on lipid and lipoprotein metabolism in subjects on statin treatment

2008 ◽  
Vol 100 (5) ◽  
pp. 937-941 ◽  
Author(s):  
Ariënne de Jong ◽  
Jogchum Plat ◽  
Dieter Lütjohann ◽  
Ronald P. Mensink
Keyword(s):  
Bile Acid ◽  
Plant Sterol ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Statin Treatment ◽  
Bile Acid Synthesis ◽  
Control Group ◽  
Stanol Ester

Consumption of plant sterol- or stanol-enriched margarines by statin users results in an additional LDL-cholesterol reduction of approximately 10 %, which may be larger than the average decrease of 3–7 % achieved by doubling the statin dose. However, whether this effect persists in the long term is not known. Therefore, we examined in patients already on stable statin treatment the effects of 85 weeks of plant sterol and stanol ester consumption on the serum lipoprotein profile, cholesterol metabolism, and bile acid synthesis. For this, a double-blind randomised trial was designed in which fifty-four patients consumed a control margarine with no added plant sterols or stanols for 5 weeks (run-in period). For the next 85 weeks, seventeen subjects continued with the control margarine and the other two groups with either a plant sterol (n18) or plant stanol (n19) (2·5 g/d each) ester-enriched margarine. Blood was sampled at the end of the run-in period and every 20 weeks during the intervention period. Compared with the control group, plant sterol and stanol ester consumption reduced LDL-cholesterol by 0·28 mmol/l (or 8·7 %;P = 0·08) and 0·42 mmol/l (13·1 %;P = 0·006) respectively after 85 weeks. No effects were found on plasma concentrations of oxysterols or 7α-hydroxy-4-cholesten-3-one, a bile acid synthesis marker. We conclude that long-term consumption of both plant sterol and stanol esters effectively lowered LDL-cholesterol concentrations in statin users.

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