Fecal Bile Acid Excretion Research Articles

Omega 3 Fatty Acids Promote Macrophage Reverse Cholesterol Transport in Hamster Fed High Fat Diet

The aim of this study was to investigate macrophage reverse cholesterol transport (RCT) in hamster, a CETP-expressing species, fed omega 3 fatty acids (ω3PUFA) supplemented high fat diet (HFD). Three groups of hamsters (n = 6/group) were studied for 20 weeks: 1) control diet: Control, 2) HFD group: HF and 3) HFD group supplemented with ω3PUFA (EPA and DHA): HFω3. In vivo macrophage-to-feces RCT was assessed after an intraperitoneal injection of 3H-cholesterol-labelled hamster primary macrophages.Compared to Control, HF presented significant (p<0.05) increase in body weight, plasma TG (p<0.01) and cholesterol (p<0.001) with an increase in VLDL TG and in VLDL and LDL cholesterol (p<0.001).Compared to HF, HFω3 presented significant decrease in body weight. HFω3 showed less plasma TG (p<0.001) and cholesterol (p<0.001) related to a decrease in VLDL TG and HDL cholesterol respectively and higher LCAT activity (p<0.05) compared to HF. HFω3 showed a higher fecal bile acid excretion (p<0.05) compared to Control and HF groups and higher fecal cholesterol excretion (p<0.05) compared to HF. This increase was related to higher gene expression of ABCG5, ABCA1 and SR-B1 in HFω3 compared to Control and HF groups (<0.05) and in ABCG1 and CYP7A1 compared to HF group (p<0.05). A higher plasma efflux capacity was also measured in HFω3 using 3H- cholesterol labeled Fu5AH cells.In conclusion, EPA and DHA supplementation improved macrophage to feces reverse cholesterol transport in hamster fed HFD. This change was related to the higher cholesterol and fecal bile acids excretion and to the activation of major genes involved in RCT.

Hypocholesterolemic effect of capsaicinoids by increased bile acids excretion in ovariectomized rats

This study investigated the interaction of dietary capsaicinoids with the mRNA and protein expressions of key receptors and enzymes involved in cholesterol metabolism in ovariectomized (OVX) rats. Female Sprague-Dawley rats were subjected to sham operation or ovariectomy. The sham group and OVX control group were fed with high-cholesterol diets, whereas the treatment group (control diet containing 0.01% capsaicinoids) was fed with high-cholesterol plus 0.01% capsaicinoids diet for 21 days. Capsaicinoids significantly decreased the body weight gain, plasma total cholesterol, LDL cholesterol, and triacylglycerol without affecting the high-density lipoprotein cholesterol in the OVX rats. The change in plasma lipoprotein profile was accompanied by a greater excretion of total bile acid in feces and small intestinal contents. Western blot and real-time PCR analyses revealed that capsaicinoids significantly enhanced the expressions of hepatic cholesterol 7α-hydroxylase and transient receptor potential vanilloid type-1 but did not affect the expression of 3-hydroxy-3-methylglutaryl-CoA reductase in the OVX rats. Capsaicinoids have cholesterol-lowering effects in OVX rats. The hypocholesterolemic activity of capsaicinoids is caused by the stimulating conversion of cholesterol to bile acids by upregulation of cholesterol 7α-hydroxylase expression and the increase in fecal total bile acid excretion.

Amaranth Oil Increased Fecal Excretion of Bile Acid but Had No Effect in Reducing Plasma Cholesterol in Hamsters

Hamsters were fed for 4weeks on four different diets: control (C) (balanced diet containing 20% corn oil as the lipid source), hypercholesterolemic (H) (identical to C but containing 12% coconut oil, 8% corn oil and 0.1% cholesterol as the lipid source), amaranth oil (A) (identical to H without corn oil but with amaranth oil), and squalene (S) (identical to H but admixed with squalene in the ratio found in amaranth oil). There were no significant differences in lipid profile, and in the cholesterol excreted in the animals' feces from amaranth oil (A) and squalene (S) groups. Fecal excretion of bile acids was greater in the amaranth oil (A) and squalene groups (S) as compared to the other groups. The scores of steatosis and parenchymal inflammation observed in the amaranth oil (A) and squalene groups (S) were superior to the ones observed in the other groups. Our findings demonstrated that amaranth oil, and its component squalene, increased the excretion of bile acids but did not have a hypocholesterolemic effect in hamsters fed on a diet containing high amounts of saturated fat and cholesterol.

Plasma and hepatic cholesterol-lowering effects of tomato pomace, tomato seed oil and defatted tomato seed in hamsters fed with high-fat diets

The cholesterol-lowering effects of tomato pomace (TP), tomato seed oil (TSO) and defatted tomato seed (DTS) were determined in male Golden Syrian hamsters. Hamsters fed high-fat diets containing 10% TSO or 18% DTS were compared to a diet containing 10% corn oil and 10% microcrystalline cellulose (control 1), 42% TP were compared to 25% microcrystalline cellulose (control 2). TP, TSO and DTS reduced hepatic total cholesterol (TC) content. DTS also lowered plasma TC and low-density lipoprotein cholesterol (LDL-C) concentrations. Fecal excretion of lipid, bile acid and cholesterol increased in the DTS group compared to control 1. DTS-fed hamsters had higher levels of hepatic CYP7A1, CYP51, ABCB11, and ABCG5 gene expression than control, suggesting both hepatic bile acid and cholesterol synthesis increased due to increased fecal excretion of bile acid and cholesterol. The results suggest that protein, dietary fibre or phenolic compounds in DTS may be responsible for plasma cholesterol decrease.

魚油とわかめ摂取がラット肝臓脂質濃度と糞中胆汁酸排泄におよぼす影響

魚油とわかめ摂取がラット肝臓脂質濃度と糞中胆汁酸排泄におよぼす影響

The hypocholesterolemic effect of capsaicinoids in ovariectomized rats fed with a cholesterol-free diet was mediated by inhibition of hepatic cholesterol synthesis

Previous studies showed that capsaicinoid supplementation favorably modifies the plasma lipoprotein profile. The present study investigated the effect of capsaicinoids on plasma lipids and gene expressions of key receptors and enzymes involved in cholesterol metabolism in ovariectomized (OVX) rats. OVX rats were fed with a cholesterol-free diet and orally administered 0 mg kg(-1) bw (OVX-CON), 5 mg kg(-1) bw (OVX-LD), 10 mg kg(-1) bw (OVX-MD), and 15 mg kg(-1) bw (OVX-HD) capsaicinoids daily for 28 days. As the capsaicinoids dose increased, body weight gain and concentrations of plasma triglyceride, total cholesterol, and low-density lipoprotein cholesterol, as well as total lipid accumulation were significantly decreased. In addition, the mRNA levels of hepatic 3-hydroxyl-3-methylglutaryl CoA reductase and cholesterol-7α-hydroxylase were down-regulated, whereas those of transient receptor potential vanilloid type-1, ileal apical sodium-dependent bile acid transporter, and intestinal bile acid binding protein were up-regulated. The excretion of small intestinal bile acid contents and fecal bile acid also decreased. These results suggest that capsaicinoids can prevent ovarian hormone deficiency-induced hypercholesterolemia by inhibiting the hepatic cholesterol synthesis.

Effect of Soymilk Fermented with Lactobacillus plantarum P-8 on Lipid Metabolism and Fecal Microbiota in Experimental Hyperlipidemic Rats

We recently identified a novel probiotic strain Lactobacillus plantarum P-8 (L. plantarum P-8), which has been characterized in detail with regard to its probiotic potential. In the present study, soymilk fermented with L. plantarum P-8 was examined for its effects on diet-induced hyperlipidemia in Wistar rats. The experimental animals were divided into four groups: control group (C group), model group (M group), soymilk group (SM group) and fermented soymilk group (FSM group). The serum lipid levels, hepatic fat deposition, serum oxidative stress parameters, hepatic marker enzymes levels, organ indices, gut bacteria and fecal fat contents were analyzed. Fermented soymilk reduced the concentration of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in serum, with a significant elevation in high-density lipoprotein cholesterol (HDL) concentration. Our results also suggested the beneficial effects of fermented soymilk on the liver function, hyperlipidemia-induced oxidative stress and intestinal bacteria. Moreover, fermented soymilk could enhance the fecal excretion of TC, TG and bile acids. These findings demonstrated that soymilk fermented with L. plantarum P-8 was effective in improving the lipid metabolism in hyperlipidemic rats. The hypolipidemic effect of fermented soymilk was partly due to the inhibition of dietary fats absorption and regulation of fecal fats excretion mediated by gut bacteria.

The Ileal Lipid Binding Protein Is Required for Efficient Absorption and Transport of Bile Acids in the Distal Portion of the Murine Small Intestine

The ileal lipid binding protein (ilbp) is a cytoplasmic protein that binds bile acids with high affinity. However evidence demonstrating the role of this protein in bile acid transport and homeostasis is missing. We created a mouse strain lacking ilbp (Fabp6−/− mice) and assessed the impact of ilbp deficiency on bile acid homeostasis and transport in vivo. Elimination of ilbp increased fecal bile acid excretion (54.2%, P<0.05) in female but not male Fabp6−/− mice. The activity of cholesterol 7α-hydroxylase (cyp7a1), the rate-controlling enzyme of the classical bile acid biosynthetic pathway, was significantly increased in female (63.5%, P<0.05) but not in male Fabp6−/− mice. The amount of [3H]taurocholic acid (TCA) excreted by 24 h after oral administration was 102% (P<0.025) higher for female Fabp6−/− mice whereas it was 57.3% (P<0.01) lower for male Fabp6−/− mice, compared to wild-type mice. The retained fraction of the [3H]TCA localized in the small and large intestines was increased by 22% (P<0.02) and decreased by 62.7% (P<0.01), respectively, in male Fabp6−/− mice relative wild-type mice, whereas no changes were seen in female Fabp6−/− mice. Mucosal to serosal bile acid transport using everted distal gut sacs was decreased by 74% (P<0.03) in both sexes of Fabp6−/− mice as compared to wild-type mice. The results demonstrate that ilbp is involved in the apical to basolateral transport of bile acids in ileal enterocytes, and is vital for the maintenance of bile acid homeostasis in the enterohepatic circulation (EHC) in mice.

Amaranth Grain Brings Health Benefits to Young Normolipidemic Rats

This paper reports the impact of an extruded amaranth (Amaranthus spp) supplement on intestinal bile and fatty acids of normolipidemic rats. Forty-eight rats were fed either a control diet AIN 93-G (12 or 18% protein), or one of two levels of supplemental extruded amaranth flour for 48 days. Plasma glucose, insulin, total cholesterol, their fractions, and triacylglycerols, liver weight and lipid content, cecum short-chain fatty acids and fecal excretion of bile acids were determined. While no significant differences in the levels of plasma triacylglycerols, glucose or insulin, and liver parameters due to the diet were detected. Although amaranth promotes reduction of both total and LDL serum cholesterol, increased production of butyric acid in cecum and fecal excretion of deoxycholic acid in the feces. These results suggest that amaranth used routinely as a supplement to the standard casein diet could have a health-promoting value in the normal rat.

Disruption of Stard10 gene alters the PPARα-mediated bile acid homeostasis

STARD10, a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) protein family, is highly expressed in the liver and has been shown to transfer phosphatidylcholine. Therefore it has been assumed that STARD10 may function in the secretion of phospholipids into the bile. To help elucidate the physiological role of STARD10, we produced Stard10 knockout mice (Stard10−/−) and studied their phenotype. Neither liver content nor biliary secretion of phosphatidylcholine was altered in Stard10−/− mice. Unexpectedly, the biliary secretion of bile acids from the liver and the level of taurine-conjugated bile acids in the bile were significantly higher in Stard10−/− mice than wild type (WT) mice. In contrast, the levels of the secondary bile acids were lower in the liver of Stard10−/− mice, suggesting that the enterohepatic cycling is impaired. STARD10 was also expressed in the gallbladder and small intestine where the expression level of apical sodium dependent bile acid transporter (ASBT) turned out to be markedly lower in Stard10−/− mice than in WT mice when measured under fed condition. Consistent with the above results, the fecal excretion of bile acids was significantly increased in Stard10−/− mice. Interestingly, PPARα-dependent genes responsible for the regulation of bile acid metabolism were down-regulated in the liver of Stard10−/− mice. The loss of STARD10 impaired the PPARα activity and the expression of a PPARα-target gene such as Cyp8b1 in mouse hepatoma cells. These results indicate that STARD10 is involved in regulating bile acid metabolism through the modulation of PPARα-mediated mechanism.

Mig-6 Plays a Critical Role in the Regulation of Cholesterol Homeostasis and Bile Acid Synthesis

The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.

Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A‐I variant

Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA-I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines.

Effect of Lactobacillus plantarum P‐8 on lipid metabolism in hyperlipidemic rat model

AbstractProbiotics have been reported to play an important role in the prevention of metabolic disorders. We recently identified a novel probiotic strain Lactobacillus plantarum (L. plantarum) P‐8. The objective of this study was to determine the effects of L. plantarum P‐8 on lipid metabolism of rats fed with high fat diet. All experimental rats were divided into three groups: control group, model group, and L. plantarum P‐8 group. Changes in serum lipid levels, hepatic lipid deposition, serum oxidative stress‐related parameters, activities of liver function marker enzymes, organ indices, gut microflora, and fecal lipids were assessed. Compared with model group, L. plantarum P‐8 exhibited hypolipidemic effects by lowering serum total cholesterol (TC), triglyceride (TG), and low‐density lipoprotein cholesterol levels, accompanied with elevation of high‐density lipoprotein cholesterol level. L. plantarum P‐8 also exerted beneficial effects against high‐fat diet‐induced oxidative stress, curtailed the accumulation of liver lipids and protected healthy liver function. Moreover, L. plantarum P‐8 was able to regulate intestinal bacteria and enhance the fecal excretion of TC, TG, and bile acid. These findings indicate that L. plantarum P‐8 may represent a potential therapeutic agent for controlling hyperlipidemia.

Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice

Liver X receptor (LXR)α regulates the genes involved in cholesterol, fatty acid and glucose metabolism. Soy protein (SP) consumption reduces the hepatic accumulation of cholesterol and triacylglycerol, and improves insulin sensitivity. However, it is not known whether these effects are mediated via LXRα. We therefore investigated whether the consumption of SP regulates metabolic changes in cholesterol metabolism and insulin sensitivity via LXRα. Wild-type (WT) and Lxrα(-/-) (Lxrα, also known as Nr1h3) mice were fed an SP diet with or without cholesterol for 28 days. The expression of LXRα target genes was measured in liver and intestine, as were hepatic lipid content and faecal bile acid concentration. Oral glucose and insulin tolerance tests were also performed. Hepatocytes were used to study the effect of isoflavones on LXR activity. The livers of WT and Lxrα(-/-) mice fed an SP high-cholesterol diet showed less steatosis than those fed casein. The SP diet increased the expression of the ATP-binding cassette (ABC) sub-family genes Abca1, Abcg5 and Abcg8 in the liver and intestine, as well as increasing total faecal bile acid excretion and insulin sensitivity in WT mice compared with mice fed a casein diet. However, these effects of SP were not observed in Lxrα(-/-) mice. The SP isoflavone, genistein, repressed the activation of LXRα target genes by T0901317, whereas it stimulated the activation of LXRβ target genes. The AMP-activated protein kinase inhibitor, compound C, had the opposite effects to those of genistein. Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform.

High molecular weight persimmon tannin is a potent hypolipidemic in high-cholesterol diet fed rats

Aimed to elucidate whether high molecular weight persimmon tannin (HMWPT) is responsible for the hypolipidemic effect of consuming persimmon fruit, the effects of HMWPT on high-cholesterol diet fed rats were investigated. Male Sprague–Dawley rats were fed a 2% high-cholesterol diet and treated with different dosages of HMWPT or without HMWPT for 9weeks, lipids and antioxidant profiles were examined and the morphology of livers was checked as well. The results indicated that HMWPT effectively reduced serum and hepatic triglyceride, total cholesterol and low density lipoprotein cholesterol while increased the serum and hepatic high density lipoprotein cholesterol (p<0.05). In addition, 100mg/kg body weight per day of HMWPT treatment could significantly enhance the serum lecithin cholesterol acyl transferase (LCAT) activity and fecal bile acids excretion (p<0.05). Meanwhile, accumulation of hepatic lipid droplets and hepatic steatosis induced by high-cholesterol diet was inhibited markedly by HMWPT. Furthermore, high-cholesterol diet induced oxidative stress in rats but HMWPT significantly increased the decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), elevated the lowered total anti-oxidation capability (T-AOC), (p<0.05), and decreased the raised malondialdehyde (MDA) levels (p<0.05) in serum or liver. These results suggested that HMWPT was responsible for the hypocholesterolemic effect of persimmon fruit and it might exert the hypolipidemic effect through stimulating serum LCAT activity, enhancing fecal bile acids excretion and improving antioxidant profile.

Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1(-/-) mice fed low levels of cholic acid.

Cholesterol 7α-hydroxylase (CYP7A1) is the initiating and rate-limiting enzyme in the neutral pathway that converts cholesterol to primary bile acids (BA). CYP7A1-deficient (Cyp7a1(-/-)) mice have a depleted BA pool, diminished intestinal cholesterol absorption, accelerated fecal sterol loss, and increased intestinal cholesterol synthesis. To determine the molecular and physiological effects of restoring the BA pool in this model, adult female Cyp7a1(-/-) mice and matching Cyp7a1(+/+) controls were fed diets containing cholic acid (CA) at modest levels [0.015, 0.030, and 0.060% (wt/wt)] for 15-18 days. A level of just 0.03% provided a CA intake of ~12 μmol (4.8 mg) per day per 100 g body wt and was sufficient in the Cyp7a1(-/-) mice to normalize BA pool size, fecal BA excretion, fractional cholesterol absorption, and fecal sterol excretion but caused a significant rise in the cholesterol concentration in the small intestine and liver, as well as a marked inhibition of cholesterol synthesis in these organs. In parallel with these metabolic changes, there were marked shifts in intestinal and hepatic expression levels for many target genes of the BA sensor farnesoid X receptor, as well as genes involved in cholesterol transport, especially ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG8. In Cyp7a1(+/+) mice, this level of CA supplementation did not significantly disrupt BA or cholesterol metabolism, except for an increase in fecal BA excretion and marginal changes in mRNA expression for some BA synthetic enzymes. These findings underscore the importance of using moderate dietary BA levels in studies with animal models.

Hypocholesterolaemic effect of yoghurt containing Bifidobacterium pseudocatenulatum G4 or Bifidobacterium longum BB536

The effect of a yoghurt supplement containing Bifidobacterium pseudocatenulatum G4 or Bifidobacterium longum BB536 on plasma lipids, lipid peroxidation and the faecal excretion of bile acids was examined in rats fed a cholesterol-enriched diet. After 8weeks, the rats in the positive control (PC) group who were fed the cholesterol-enriched diet showed significant increases in plasma total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and malondialdehyde (MDA). However, groups fed a cholesterol-enriched diet supplemented with yoghurt containing B. pseudocatenulatum G4 or B. longum BB536 had significantly lower plasma TC, LDL-C, very-low-density lipoprotein (VLDL) cholesterol, and MDA than had the PC group after 8weeks of treatment. In addition, faecal excretion of bile acids was markedly increased in the rats fed the yoghurt containing B. pseudocatenulatum G4 or B. longum BB536 as compared to the PC and NC groups.

Abstract 307: Influence of Dendritic Cells on Cholesterol Absorption and Excretion: Implication in Atherogenesis

Atherosclerosis represents the chronic pathophysiological process implicated in the majority of cardiovascular (CV) diseases and constitutes one of the leading causes of death in the world. The development of atherosclerotic lesions is characterized by an accumulation of extracellular and intracellular lipids in the arterial wall. These phenomena are associated with a strong local immuno-inflammatory response characterized by the recruitment of various populations of leucocytes including monocytes, macrophages and dendritic cells (DCs). DCs are central to the regulation of immunity and the polarization of the immune response. We recently demonstrated that the longevity/depletion of DCs directly impacts plasma cholesterol levels, which is the main risk factor for atherosclerosis. To gain insight into the cellular and molecular mechanisms underlying the inverse relationship between DC numbers and cholesterolemia, we have evaluated the impact of DCs on cholesterol homeostasis, using CD11c-hBcl2/apoE KO mice, in which specific DC-expression of the anti-apoptotic transgene hBcl2 increase their longevity and numbers. Firstly, we quantified DC populations in the liver and in the intestine, which are the main organs involved in cholesterol metabolism. Secondly, we measured the rates of dietary cholesterol absorption, tissue cholesterol content and sterol and bile salt excretion. Thirdly, we analysed the expression of genes associated with cholesterol metabolism in the liver and the intestine. We found an increase of DC numbers in the liver and in the intestine in the CD11c-hBcl2 apoE KO mice relative to control apoE KO mice. This increase of DC numbers was associated with reduced intestinal cholesterol absorption and fecal bile acid excretion, but also with greater fecal excretion of sterols. Finally, there were no differences in the cholesterol content of the intestine and the liver. Our results suggest that the decrease in plasma cholesterol level in CD11c-hBcl2 apoE KO mice relative to apoE KO mice could be due to both a decrease of intestinal cholesterol absorption and an increase in sterol excretion. The role of intestinal DCs in dietary cholesterol absorption and excretion is presently under investigation but the present study reveal that DCs are central to the atherosclerotic process, because they are implicated in cholesterol metabolism.

Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism

Blocking intestinal bile acid (BA) absorption by inhibiting or inactivating the apical sodium-dependent BA transporter (Asbt) classically induces hepatic BA synthesis. In contrast, blocking intestinal BA absorption by inactivating the basolateral BA transporter, organic solute transporter alpha-beta (Ostα-Ostβ) is associated with an altered homeostatic response and decreased hepatic BA synthesis. The aim of this study was to determine the mechanisms underlying this phenotype, including the role of the farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15). BA and cholesterol metabolism, intestinal phenotype, expression of genes important for BA metabolism, and intestinal FGF15 expression were examined in wild type, Ostα(-/-), Fxr(-/-), and Ostα(-/-)Fxr(-/-) mice. Inactivation of Ostα was associated with decreases in hepatic cholesterol 7α-hydroxylase (Cyp7a1) expression, BA pool size, and intestinal cholesterol absorption. Ostα(-/-) mice exhibited significant small intestinal changes, including altered ileal villus morphology, and increases in intestinal length and mass. Total ileal FGF15 expression was elevated almost 20-fold in Ostα(-/-) mice as a result of increased villus epithelial cell number and ileocyte FGF15 protein expression. Ostα(-/-)Fxr(-/-) mice exhibited decreased ileal FGF15 expression, restoration of intestinal cholesterol absorption, and increases in hepatic Cyp7a1 expression, fecal BA excretion, and BA pool size. FXR deficiency did not reverse the intestinal morphological changes or compensatory decrease for ileal Asbt expression in Ostα(-/-) mice. These results indicate that signaling via FXR is required for the paradoxical repression of hepatic BA synthesis but not the complex intestinal adaptive changes in Ostα(-/-) mice.

Tu1419 Relationship of Synthesis and Fecal Excretion of Bile Acids to Fecal Fat and Weight, and Genetic Variations in Bile Acid Regulatory Pathways in Irritable Bowel Syndrome With Diarrhea (IBS-D) and Constipation (IBS-C)

Tu1419 Relationship of Synthesis and Fecal Excretion of Bile Acids to Fecal Fat and Weight, and Genetic Variations in Bile Acid Regulatory Pathways in Irritable Bowel Syndrome With Diarrhea (IBS-D) and Constipation (IBS-C)