Increased Bile Acid Excretion Research Articles

Obicetrapib Alone and in Combination with Ezetimibe Reduces Non-HDL-Cholesterol by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and cardiovascular risk. It reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, also reducing LDL-C levels. The current study elucidates the mechanism for decreases in non-HDL-C by obicetrapib alone and with ezetimibe in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib (2 mg/kg/day), ezetimibe (1 mg/kg/day), or obicetrapib with ezetimibe.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-42%, -23% and -62%).Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 (98% and 81%). Obicetrapib, ezetimibe, and the combination enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice was observed, and was more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.Conclusions: Obicetrapib alone and with ezetimibe reduced non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels, and enhanced fecal bile acid and neutral sterol excretion.

Evaluation of probiotic bifidobacteria strains from Iranian traditional dairy products for their anti-hyperlipidemic potential.

This study investigated the therapeutic potential of probiotic bifidobacteria, isolated from Iranian fermented dairy products, in a hyperlipidemic animal model. Bifidobacterium strains were extracted from traditional dairy samples and screened using physiological and phenotypic examinations, 16S rRNA analysis, and probiotic properties such as tolerance to gastrointestinal juice, antimicrobial activity, and antibiotic susceptibility. The ability of the screened bifidobacteria to reduce serum and liver lipids in vivo was tested using male Wistar rats. Six strains of bifidobacteria were isolated from traditional Iranian fermented dairy. These strains showed promising in vitro activity in lowering triglyceride and cholesterol, tolerance to simulated gastrointestinal juice, the ability to adhere to Caco-2 cells, acceptable antibiotic susceptibility, and a broad spectrum of antibacterial activity. The diet supplemented with isolated bifidobacteria significantly reduced serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), liver tissue lipid levels, and hepatic enzymes in animals when compared to a high-fat diet without strains (p < 0.01). Additionally, the potential probiotic-supplemented diet significantly increased bile acid excretion in the feces and upregulated hepatic CYP7A1 expression levels (p < 0.05), while NPC1L1, ACAT2, and MTP gene expressions in small intestinal cells were downregulated (p < 0.05). Bifidobacteria isolated from Iranian traditional dairy showed potential for use in the production of fermented foods that have hypolipemic activity in the host.

Inulin ameliorates metabolic syndrome in high-fat diet-fed mice by regulating gut microbiota and bile acid excretion.

Background: Inulin is a natural plant extract that improves metabolic syndrome by modulating the gut microbiota. Changes in the gut microbiota may affect intestinal bile acids. We suggest that inulin may improve metabolism by inducing bile acid excretion by gut microbes. Methods: Male C57/BL mice were fed either a high-fat diet (60% calories) or a regular diet for 16weeks, with oral inulin (10% w/w). At the end of the experiment, the gene expression levels (FGF15, CD36, Srebp-1c, FASN, and ACC) in the liver and intestines, as well as the serum levels of triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, total cholesterol, and free fatty acids, were collected. The expression of FGF15 was examined using Western blot analysis. The fat distribution in the liver and groin was detected by oil red and hematoxylin and eosin staining. Simultaneously, the levels of serum inflammatory factors (alanine aminotransferase and aspartate aminotransferase) were detected to explore the side effects of inulin. Results: Inulin significantly improved glucose tolerance and insulin sensitivity, and decreased body weight and serum TG and LDL levels, in mice fed normal diet. Furthermore, inulin increased the α-diversity of the gut microbiota and increased the fecal bile acid and TG excretion in inulin-treated mice. In addition, inulin significantly reduced lipid accumulation in liver and inguinal fat, white fat weight, and hepatic steatosis. Western blot analysis showed that inulin reduced the expression of FGF15, a bile acid reabsorption protein. Conclusion: Inulin ameliorates the glucose and lipid metabolic phenotypes of mice fed a normal diet, including decreased intestinal lipid absorption, increased glucose tolerance, increased insulin sensitivity, and decreased body weight. These changes may be caused by an increase in bile acid excretion resulting from changes in the gut microbiota that affect intestinal lipid absorption.

Dietary Grape Seed Tannins Affect Lipoproteins, Lipoprotein Lipases and Tissue Lipids in Rats Fed Hypercholesterolemic Diets , ,

The effects of monomeric and polymeric grape seed tannins on rat plasma lipoproteins, lipoprotein lipase, hepatic lipase and aortic and hepatic lipid concentration were studied. Male Sprague-Dawley rats received either a normal diet (with no added cholesterol and no tannins), a control diet (hypercholesterolemic diet) or hypercholesterolemic diets supplemented with 2% tannin monomers or 2% polymers 3 or 9 wk. Plasma total cholesterol, triacylglycerol, LDL cholesterol and VLDL concentrations were significantly higher and the HDL cholesterol concentration lower in controls and in rats fed the diet supplemented with monomers compared with rats fed polymeric tannins at both time points. Lipoprotein lipase and hepatic lipase activities were significantly higher in control and in monomer-fed groups than in the polymer-fed group. Hepatic and aortic cholesterol and triacylglycerol concentrations were significantly higher in control rats and those fed monomers than in the polymer-fed group. Moreover, plasma HDL cholesterol and hepatic lipase activity were closely associated with low aortic cholesterol and triacylglycerol in rats fed polymeric tannins. These rats also exhibited greater fecal excretion of cholesterol and especially bile acids than the control or monomer-fed groups. Thus dietary grape seed tannins have a pronounced anti-hypercholesterolemic effect by enhancing reverse cholesterol transport and also by reducing intestinal cholesterol absorption and increasing bile acid excretion.

The Supplementation of FloraMax-B11 Did Not Affect the Bile Acid Neosynthesis and the Enterohepatic Circulation in Broiler Chickens.

Most probiotics possess bile salt hydrolase enzymes and may increase bile acid excretion and negatively affect fat digestion and absorption. Therefore, the study objective was to determine the time course effects of a commercial probiotic (P) FloraMax-B11 (FM) supplementation on bile acid neosynthesis and enterohepatic circulation in broiler chickens. Fertile Ross 708 eggs were incubated under standard commercial conditions. At hatch, chicks (n = 550) were randomly assigned to 5 treatment groups (n = 5 replicates per treatment group) with 22 birds per pen. The 5 treatment groups consisted of: control group (C, normal water from hatch to 35 days of age without supplements); P3, water supplemented with FM for the first 3 days post-hatch followed by normal water until day 35; P10, water supplemented with FM for the first 10 days post-hatch followed by normal water until day 35; P35, water supplemented with FM from hatch to day 35; and AGP, water supplemented with antibiotic growth promoter (AGP) from hatch until day 35. Ileum, liver, and plasma were collected at hatch, days 3, 10, 21, and 35 post-hatch. The relative mRNA expression of genes involved in bile acid synthesis (CYP7A1, CYP8B1, FXR, FGFR4, and FGF19) and transport (ASBT, I-BABP, OSTα, OSTβ, and BSEP) as well as ileal deoxycholic acid and plasma cholic acid were determined. There was no FM and AGP interaction for any of the response criteria. No FM or AGP effects were observed (p &gt; 0.05) for any genes, except FGF19, which expression was increased (p &lt; 0.0001) in AGP compared to P35. No FM or AGP effects were observed (p &gt; 0.05) for levels of deoxycholic and cholic acids. However, all the genes, deoxycholic acid, and plasma cholic acid were affected by age (p &lt; 0.0001). In general, the data indicate that FM did not negatively impact bile acid metabolism and enterohepatic circulation, which appeared to be age dependent. However, more research should be conducted to confirm these results and investigate the effects of FM on bile acid metabolism, fat digestion, and intestinal microbiota in broiler chickens.

The Hypolipidemic and Antioxidant Activity of Wheat Germ and Wheat Germ Protein in High-Fat Diet-Induced Rats.

Background: So far, no articles have discussed the hypolipidemic effect of wheat germ protein in in vivo experiments. Objective: In this study, we investigated the effects of wheat germ protein (WGP, 300 mg/kg/day) and wheat germ (WG, 300 mg/kg/day) on cholesterol metabolism, antioxidant activities, and serum and hepatic lipids in rats fed a high-fat diet through gavage. Methodology: We used 4-week-old male Wistar 20 rats in our animal experiment. Biochemical indicators of fecal, serum and liver were tested by kits or chemical methods. We also conducted the cholesterol micellar solubility experiment in vitro. Results: After 28 days of treatment, our results showed that WGP significantly reduced the serum levels of total cholesterol (p < 0.05) and nonhigh-density lipoprotein cholesterol (p < 0.05), improved the enzymatic activities of cholesterol 7-α hydroxylase (p < 0.01) and low-density lipoprotein receptor (p < 0.01) and increased bile acid excretion in feces (p < 0.05). Conclusion: WG did not significantly increase bile acid excretion in feces or decrease serum levels of total cholesterol. Moreover, WGP and WG both presented significant antioxidant activity in vivo (p < 0.05) and caused a significant reduction in cholesterol micellar solubility in vitro (p < 0.001). Therefore, WGP may effectively prevent hyperlipidemia and its complications as WGP treatment enhanced antioxidant activity, decreased the concentration of serum lipids and improved the activity of enzymes involved in cholesterol metabolism.

Plants of the Spontaneous Flora with Beneficial Action in the Management of Diabetes, Hepatic Disorders, and Cardiovascular Disease.

The current pharmacological agents advised for the management of diabetes as well as cardiovascular and hepatic diseases are subject to numerous studies for safety and efficacy. Therefore, it is worth looking into alternative therapeutic aids such as natural products of medicinal plants. By a broad review of in vitro and in vivo studies on the various dandelion, chicory, and mulberry extracts, this work highlights their bioactive compounds and therapeutic action when used as a prevention and management aid in public health such as diabetes, cardiovascular disease, and hepatic disorders like non-alcoholic steatohepatitis. Natural products of dandelion leaves and root extracts can suppress the development of liver cancer, decrease insulin resistance, and suppress total triglyceride and cholesterol levels. Recent studies on mulberry leaves extracts indicated that they could decrease palmitic acid-induced lipotoxicity, increase total cholesterol and bile acid excretion, improve superoxide dismutase expression, and improve insulin resistance. Chicory root extracts boost satiety, reverse insulin resistance, and augment lipid metabolism thanks to their contents in chicoric acid, chlorogenic acid, and polysaccharides. Taraxacum officinale L., Morus nigra L., and Cichorium intybus L. present hepatoprotective, anti-inflammatory, antioxidant, hypolipidemic, and hypoglycemic activities and are shown to be advantageous in the management of obesity, dyslipidemia, Type 2 diabetes, and non-alcoholic fatty liver diseases. These plants are commonly available in the European spontaneous flora and more attention could be paid to their natural products.

PSXI-28 Commercial grain-free diet improved taurine status, but increased bile acid excretion when fed to Labrador Retrievers

Abstract In 2018 the Food and Drug Administration (FDA) released a statement that grain-free diets may be related to the increased incidence of dilated cardiomyopathy (DCM) in dogs. This statement was made despite all implicated diets meeting nutrient requirements published by the Association of American Feed Controls Official (AAFCO) and enforced by State Officials. Many of these dogs presented with low plasma or whole blood taurine concentrations, and as such, we hypothesized that feeding these diets would result in reduced taurine status over a 26 wk feeding period. The objective of this study was to determine the effects of feeding a grain-free diet to large breed dogs on taurine status and overall health. Eight Labrador Retrievers (4 males, 4 females; Four Rivers Kennel, MO) were individually housed and fed a commercial complete and balanced grain-free diet (Acana Pork and Squash formula; APS; moisture 8.40%, crude protein 37.81%, crude fat 18.78%, ash 8.06%, and total dietary fiber 11.40%) for 26 weeks. Fasted blood samples were collected at week 0 and 26 for analyses of plasma and whole blood taurine. Urine was collected by free catch and analyzed for taurine and creatinine. Fresh fecal samples were collected and analyzed for bile acids. Data were analyzed using the GLIMMIX procedure with repeated measures in SAS (v. 9.4). Dogs were healthy throughout the duration of the trial. Urinary taurine to creatinine ratio did not change throughout the feeding period (wk 0 = 0.25 vs. wk 26 = 0.28). Fecal bile acid excretion increased after 26 weeks of feeding APS to dogs. Despite the higher fecal excretion of bile acids, plasma and whole blood taurine increased over the 26 wk feeding period. In conclusion, feeding APS for 26 wk results in increased taurine status in large breed dogs, despite higher excretion of fecal bile acids.

Fecal Bile Acid Testing in Assessing Patients With Chronic Unexplained Diarrhea: Implications for Healthcare Utilization.

Bile acid (BA) diarrhea is the cause in ∼26% of chronic unexplained (nonbloody) diarrhea (CUD) based on SeHCAT testing. To assess fecal BA excretion and healthcare utilization in patients with CUD. In a retrospective review of 1,071 consecutive patients with CUD who completed 48-hour fecal BA testing, we analyzed the symptoms, diagnostic tests performed, and final diagnoses. After 135 patients were excluded because of mucosal diseases, increased BA excretion was identified in 476 (51%) of the 936 patients with CUD: 29% with selective increase in primary BA and 22% with increased total BA excretion (35% with normal primary BA excretion). There were no differences in demographics, clinical symptoms, or history of cholecystectomy in patients with elevated total or selective primary fecal BA excretion compared with patients with normal excretion. Before the 48-hour fecal BA excretion test was performed, patients completed on average 1.2 transaxial imaging, 2.6 endoscopic procedures, and 1.6 miscellaneous tests/person. Less than 10% of these tests identified the etiology of CUD. Total fecal BAs >3,033 µmol/48 hour or primary BAs >25% had a 93% negative predictive value to exclude mucosal disease. Among patients with increased fecal BA excretion, >70% reported diarrhea improved with BA sequestrant compared with 26% with normal fecal BA excretion. Patients with selective elevation in primary fecal BAs were 3.1 times (95% confidence interval, 1.5-6.63) more likely to respond to BA sequestrant therapy compared with those with elevated total fecal BAs. Increased fecal BA excretion is frequent (51%) in patients with CUD. Early 48-hour fecal BA evaluation has the potential to decrease healthcare utilization in CUD.

Coconut milk gavage enhanced fecal bile excretion by modulating hepatic Fxr expression but failed to improve fasting serum cholesterol profile in C57BL/6 mice

The consumption of coconut milk has long been regarded as detrimental to cardiovascular health due to its high saturated fatty acid content. Contradictorily, emerging evidences have highlighted that the fatty acids in coconut lipids, which comprise mostly of medium-chain fatty acids (MCFA), may be beneficial to the regulation of serum cholesterol. To identify the potential health effect of coconut milk on lipid metabolism, this current study employed an intragastric gavage method on C57BL/6 mice to investigate the physiological and molecular alteration in the mice subject after 8 weeks of gavage intervention. The supplementation of coconut milk did not affect the levels of serum triglyceride, but it induced the total serum cholesterol after 2 weeks of treatment. The serum cholesterol level subsequently plateaued, but an increase in bile acid excretion was observed, most likely through the modulation of bile regulating genes, i.e. farnesoid X receptor (Fxr) and Cyp7a1. Despite that, the total cholesterol to HDL cholesterol ratio of coconut milk group was comparable to that of the light cream group. In short, coconut milk supplementation promoted cholesterol excretion through the fecal bile route but did not significantly improve the serum cholesterol profile of C57BL/6 mice.

Abstract P287: Hypocholesterolemic Effect of Dietary Stearic Acid May Be Partly Mediated via Alterations in Fecal Bile Acid Metabolism

Introduction: Dietary fat quality has a significant impact on CVD risk. Among the saturated fatty acids (FA), we and others have documented that stearic (18:0) is unique because, unlike shorter chain FA (12:0, 14:0, 16:0), it does not raise plasma LDL-C levels, relative to monounsaturated FA, such as oleic acid (18:1). The mechanism(s) responsible for this effect are not fully elucidated. Hypothesis: We tested the hypothesis that the hypocholesterolemic effect of dietary 18:0 and 18:1 relative to 16:0 is mediated by alterations in fecal bile acid metabolism. Methods: Primary (cholic, chenodeoxycholic) and secondary bile acids (SBA: lithocholic [LA], deoxycholic [DCA]) were quantified in stool samples from a randomized controlled cross-over trial examining the effect of dietary FA on CVD risk factors. Subjects (N=20 postmenopausal women, 50-85 years, BMI 25-35kg/m 2 , LDL-C &gt;100mg/dL) consumed each diet for 35 days separated by a 2 week washout period. Diets provided 55%E carbohydrate, 15%E protein and 30%E fat with half of the fat provided by 16:0, 18:0 or 18:1, respectively. CVD risk factors (lipids, glucose, insulin, inflammatory markers) were measured using standard methodology. For fecal bile acids analysis, freeze dried samples were spiked with the corresponding deuterated internal standards, followed by an overnight extraction, purification and analysis using reversed-phase liquid chromatography coupled with electrospray ionization quadrupole time of flight mass spectrometry. Quantification was by isotopic dilution. Spearman correlation coefficients were calculated between bile acids and CVD risk factors. Results: Fecal total SBA levels were significantly lower after subjects consumed the 18:0 (4.5±3.9 umol/g) compared to the 18:1 (6.8±5.7 umol/g) diet, with intermediate levels after the 16:0 diet (5.2±3.6 umol/g). This was predominantly due to significantly lower LA, and to a lesser extent DCA levels. No detectable differences were observed in primary bile acids levels. Total, LA and DCA levels were positively correlated with insulin (r=0.38 to 0.45; p&lt;0.05), hsCRP (r=0.31 to 0.37, p&lt;0.02), TG (r=0.46 to 0.60; p&lt;0.001), VLDL-C (r=0.47 to 0.63; p&lt;0.001), TC/LDL-C (r=0.42 to 0.63; p&lt;0.001) and LDL-C/HDL-C (0.37 to 0.57; p&lt;0.001) ratios, and negatively with HDL-C (r= -0.51 to -0.44; p&lt;0.001) levels. LA levels were also positively correlated with LDL-C levels (r=0.33; p=0.011). Conclusion: These data suggest that the hypocholesterolemic effect of dietary 18:0 was not mediated by increased bile acid excretion as was observed with dietary 18:1. Instead, dietary 18:0 appears to have an inhibitory effect on hydrophobic SBA synthesis in the intestine, which in turn could reduce the efficiency of cholesterol solubilization and thus cholesterol absorption. Further studies on the effects of dietary 18:0 on gut microbiome populations involved in SBA synthesis are warranted.

Protective effects and action mechanism of extract from Tibetan medicine Yajima(Chrysosplenium nudicaule) on mice with intrahepatic cholestasis induced by ANIT

Chrysosplenium nudicaule,Tibetan name " Yajima",is recorded as an effective medicine for the treatment of liver and gallbladder diseases by Tibetan Pharmacopoeia published in the past dynasties,but its traditional efficacy has not yet been investigated by means of modern pharmacological research methods. In this paper,the protective effect of extract of C. nudicaule(ECN) on liver injury in mice was observed by using the mice model of intrahepatic cholestasis(IC) induced by α-naphthyl isothiocyanate(ANIT) and the possible mechanism by which ECN work as the therapeutic agent was discussed. The results showed that the serum levels of AST,ALT,ALP,DBIL,TBIL and TBA of the model mice were notably reduced in dose-dependent manner(P<0. 01,P<0. 05). The activity of SOD and GSH-Px in the liver homogenate of mice was increased,while the content of MDA was decreased(P<0. 01,P<0. 05).Pathological examination of liver in mice showed that ECN could improve the pathological changes of liver tissue in mice. The mRNA expression level of genes related to bile acid metabolism were detected by RT-PCR and the results suggested that ECN could significantly increase the expression of genes such as BSEP,FXR and MRP2(P<0. 01,P<0. 05),meanwhile significantly reduce the expression of CYP7 A1(P<0. 01,P<0. 05). These results confirmed the protective effect of ECN on intrahepatic cholestasis-induced liver injury in mice,and indicated that the mechanism may be related to activating FXR and its target genes,reducing bile acid synthesis and increasing bile acid excretion. This study provides a modern pharmacological basis for the clinical application of Yajima in Tibetan medicine.

Barley β-glucan increases fecal bile acid excretion and short chain fatty acid levels in mildly hypercholesterolemic individuals.

The cholesterol-lowering effect of barley β-glucan has been proposed to be the result of a pleiotropic effect, which involves several biological mechanisms such as gut fermentation, inhibition of intestinal cholesterol absorption and increased bile acid excretion and its synthesis. However, one of the recent studies from our laboratory indicated that increased bile acid excretion and subsequent increase in its synthesis, but not the inhibition of cholesterol absorption or synthesis might be responsible for the cholesterol-lowering effect of barley β-glucan. Accordingly, the primary objective of the present study was to investigate the concentration of bile acids (BA), neutral sterols (NS) and short chain fatty acids (SCFA) excreted through the feces by mildly hypercholesterolemic subjects who consumed diets containing barley β-glucan with varying molecular weights (MW) and concentrations. In a controlled, four phase, crossover trial, 30 mildly hypercholesterolemic but otherwise healthy subjects were randomly assigned to receive breakfast containing 3 g high MW (HMW), 5 g low MW (LMW), 3 g LMW barley β-glucan or a control diet for 5 weeks. The concentrations of BA, NS and SCFA in the feces were measured at the end of each treatment phase. Compared to the other treatment groups, 3 g day-1 HMW barley β-glucan consumption resulted in increased lithocholic acid (LCA) excretion (P < 0.001) but not LMW β-glucan, even at the high dose of 5 g day-1. Increased fermentability of fibre was also evident from a significant increase in fecal total SCFA concentrations in response to the 3 g HMW β-glucan diet compared to the 3 g LMW barley β-glucan and control diet (P = 0.0015). In summary, the current results validate our previous report on the role of fecal bile acid excretion in cholesterol lowering through the consumption of barley β-glucan. In addition, increased SCFA concentrations indicate that an increase in β-glucan molecular weight promotes hindgut fermentation, which might also be playing a role in attenuating cholesterol levels.

Wholegrain oat diet changes the expression of genes associated with intestinal bile acid transport.

The molecular mechanisms underlying the cholesterol-lowering properties of oats are only partly known. To study possible pathways involved, we investigated gene expressions in the liver and small intestine of mice fed oats. Cholesterol and bile acids were analyzed in plasma and feces from LDL-receptor deficient (LDLr-/- ) mice fed Western diet with wholegrain oats. A transcriptome analysis of mRNA from liver and jejunum was performed together with quantitative RT-PCR. Oat-fed mice had lower levels of plasma lipids and increased levels of bile acids and cholesterol in feces compared with controls. Two hundred thirty nine genes in jejunum and 25 genes in liver were differentially expressed (FDR corrected p < 0.05). The most affected biological process in jejunum was lipid biosynthesis and regulation. The apical sodium-dependent bile acid transporter (ASBT, Slc10a) and the intracellular bile acid binding protein (Fabp6) were both upregulated, whereas small heterodimer partner-1 (Shp-1) and apolipoprotein CII (Apoc2) were downregulated. Whole oats attenuated responses typically induced by high-fat diet. Increased expression of genes for intestinal bile acid uptake following oat consumption suggests retention in the gut lumen rather than decreased uptake capacity as cause for the increased bile acid excretion and the concomitant reduction of plasma cholesterol.

Cheese intake lowers plasma cholesterol concentrations without increasing bile acid excretion

PurposeCheese is a dairy product with high calcium content. It has been suggested that calcium intake may increase fecal excretion of bile acids that would cause a regeneration of bile acids from hepatic cholesterol and thereby result in a lowering of plasma cholesterol concentrations. We aimed to test this hypothesis by assessing bile acid and calcium concentrations in fecal samples from humans after intake of cheese and butter. MethodsThe study was a randomized, 2 × 6 weeks crossover, dietary intervention study including 23 men and women who replaced part of their habitual dietary fat intake with 13% energy from cheese or butter. ResultsAfter 6 weeks of intervention cheese resulted in higher amounts of calcium excreted in feces compared to butter. However, no difference was observed in fecal bile acid output despite lower serum total, LDL and HDL cholesterol concentrations observed with cheese intake. ConclusionWe were not able to confirm the hypothesis that calcium from cheese increases the excretion of fecal bile acids. Therefore, the mechanisms responsible for the lowering of cholesterol concentrations with cheese compared to butter intake remains unresolved.

Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE

Liver is the sole organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or bile acids. High density lipoprotein (HDL)-derived cholesterol is the major source of biliary sterols and represents a mechanism for the removal of cholesterol from peripheral tissues including artery wall-associated macrophage foam cells. Via selective uptake through scavenger receptor BI (SR-BI), HDL-cholesterol is thought to be directly secreted into bile, and HDL cholesteryl esters (HDL-CEs) enter the hepatic metabolic pool and need to be hydrolyzed prior to conversion to bile acids. However, the identity of hepatic CE hydrolase (CEH) as well as the role of SR-BI in bile acid synthesis remains elusive. In this study we examined the role of human hepatic CEH (CES1) in facilitating hydrolysis of SR-BI-delivered HDL-CEs. Over-expression of CEH led to increased hydrolysis of HDL-[³H]CE in primary hepatocytes and SR-BI expression was required for this process. Intracellular CEH associated with BODIPY-CE delivered by selective uptake via SR-BI. CEH and SR-BI expression enhanced the movement of [³H]label from HDL-[³H]CE to bile acids in vitro and in vivo. Taken together, these studies demonstrate that SR-BI-delivered HDL-CEs are hydrolyzed by hepatic CEH and utilized for bile acid synthesis.

Effects of soy protein on lipoprotein lipids and fecal bile acid excretion in men and women with moderate hypercholesterolemia

Soy protein (SP) and low-fat dairy product consumption have been suggested to have hypocholesterolemic effects, although the responsible mechanisms are poorly understood. This randomized, controlled, parallel arm trial evaluated the effects of an insoluble fraction of SP and total milk proteins (TMPs) with high calcium content on the fasting lipid profile. It also assessed the potential contributions of increased excretion of bile acids and neutral sterols to their lipid-altering effects. Subjects with hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] 100-199 mg/dL) followed the Therapeutic Lifestyle Changes diet for 4 weeks, followed by a 2-week lead-in with 3.75 g/d colesevelam HCl. Individuals with LDL-C lowering of ≥5.0% with colesevelam HCl were randomly assigned to one of two groups after a 3-week washout: 1) 25 g/d of an insoluble fraction of partially hydrolyzed SP or 2) 25 g/d TMP. Both SP and TMP reduced atherogenic lipoproteins, as indicated by changes in total cholesterol (-7.4% and -3.6%), LDL-C (-10.9% and -5.9%), nonhigh-density lipoprotein cholesterol (-10.8% and -3.9%), and apolipoprotein B (-9.7% and -2.4%), respectively (P < .05 for between group differences except LDL-C, P = .085). No significant increases were observed in either group for fecal bile acids or neutral sterols. These results confirm that SP consumption exerts a hypocholesterolemic effect and indicate that TMP elicits a less pronounced response. However, these findings do not support the hypothesis that increased bile acid excretion is an important contributor to the hypocholesterolemic effects of either protein source.

Comparison of the Effects on Lipid Metabolism of Dietary Methionine and Cystine between Hepatoma-Bearing and Normal Rats

The effects of dietary supplementation with methionine and cystine on lipid metabolism, including the serum lipid concentration, were studied in Donryu rats subcutaneously implanted with an ascites hepatoma cell line (AH109A) for comparison with normal rats. A diet supplemented with 1.2% L-methionine or L-cystine to 20% casein was found to suppress the hepatoma-induced increases in serum triglyceride and total cholesterol concentration. The lipoprotein lipase activity in tissues was enhanced by dietary methionine and cystine, with no change in the mRNA level. Dietary methionine and cystine increased bile acid excretion into the feces with enhanced hepatic cholesterol 7alpha-hydroxylase activity. Dietary methionine and cystine affected the lipid metabolism differently in normal rats from hepatoma-bearing rats. These results suggest that dietary methionine and cystine each had a hypolipidemic effect against cancer-induced hyperlipidemia, and that the different actions observed in the hepatoma-bearing and normal rats may have been due to a metabolic abnormality caused by the cancer.

Hypocholesterolemic effects of Lactobacillus plantarum KCTC3928 by increased bile acid excretion in C57BL/6 mice

Objective We doubly coated Lactobacillus plantarum KCTC3928 with proteins and polysaccharide compounds to enhance its acid and bile resistance. The present study investigated the hypocholesterolemic effects of double-coated L. plantarum KCTC3928 in C57BL/6 mice fed a high-fat diet. The effects of live and dead bacteria were compared. Methods Six-week-old C57BL/6 male mice were divided into three groups: the control group was fed no L. plantarum KCTC3928, and the two treatment groups were orally fed live or dead L. plantarum KCTC3928 daily. Plasma and liver cholesterol and lipid levels, fecal bile acid, and gene and protein expressions were measured. Results Low-density lipoprotein cholesterol and plasma triacylglycerol levels were significantly lower in the group fed live bacteria, by 42% and 32%, respectively ( P < 0.05), and fecal bile acid excretion was accelerated (+45%). Expression of the low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase were marginally affected by the feeding of coated cells; however, the gene expression and protein levels of CYP7A1 were significantly upregulated after live L. plantarum KCTC3928 feeding (+80% for mRNA and +60% for protein expression). Conclusion Double-coated live L. plantarum KCTC3928 may have hypocholesterolemic effects in mice primarily due to induction of fecal bile acid secretion followed by increased degradation of hepatic cholesterol into bile acids. Studies in humans should confirm the effects in the future.

Farnesoid X Receptor Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor Development

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, including cyclin D1 and interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation, and tumorigenesis in the intestine, suggesting that activation of FXR by nonbile acid ligands may protect against intestinal carcinogenesis.