Ingestion of difructose anhydride III partially suppresses the deconjugation and 7α-dehydroxylation of bile acids in rats fed with a cholic acid-supplemented diet

Difructose anhydride III (DFAIII) is a prebiotic involved in the reduction of secondary bile acids (BAs). We investigated whether DFAIII modulates BA metabolism, including enterohepatic circulation, in the rats fed with a diet supplemented with cholic acid (CA), one of the 12α-hydroxylated BAs. After acclimation, the rats were fed with a control diet or a diet supplemented with DFAIII. After 2 weeks, each group was further divided into two groups and was fed diet with or without CA supplementation at 0.5 g/kg diet. BA levels were analyzed in aortic and portal plasma, liver, intestinal content, and feces. As a result, DFAIII ingestion reduced the fecal deoxycholic acid level via the partial suppression of deconjugation and 7α-dehydroxylation of BAs following CA supplementation. These results suggest that DFAIII suppresses production of deoxycholic acid in conditions of high concentrations of 12α-hydroxylated BAs in enterohepatic circulation, such as obesity or excess energy intake.

Abbreviation: BA: bile acid; BSH: bile salt hydrolase; CA: cholic acid; DCA: deoxycholic acid; DFAIII: difructose anhydride III; MCA: muricholic acid; MS: mass spectrometry; NCDs: non-communicable diseases; LC: liquid chromatography; SCFA: short-chain fatty acid; TCA: taurocholic acid; TCDCA: taurochenodeoxycholic acid; TDCA: taurodeoxycholic acid; TUDCA: tauroursodeoxychlic acid; TαMCA: tauro-α-muricholic acid; TβMCA: tauro-β-muricholic acid; TωMCA: tauro-ω-muricholic acid     

Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes

Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.     

Fish protein hydrolysate elevates plasma bile acids and reduces visceral adipose tissue mass in rats

Conjugation of bile acids (BAs) to the amino acids taurine or glycine increases their solubility and promotes liver BA secretion. Supplementing diets with taurine or glycine modulates BA metabolism and enhances fecal BA excretion in rats. However, it is still unclear whether dietary proteins varying in taurine and glycine contents alter BA metabolism, and thereby modulate the recently discovered systemic effects of BAs. Here we show that rats fed a diet containing saithe fish protein hydrolysate (saithe FPH), rich in taurine and glycine, for 26 days had markedly elevated fasting plasma BA levels relative to rats fed soy protein or casein. Concomitantly, the saithe FPH fed rats had reduced liver lipids and fasting plasma TAG levels. Furthermore, visceral adipose tissue mass was reduced and expression of genes involved in fatty acid oxidation and energy expenditure was induced in perirenal/retroperitoneal adipose tissues of rats fed saithe FPH. Our results provide the first evidence that dietary protein sources with different amino acid compositions can modulate the level of plasma bile acids and our data suggest potential novel mechanisms by which dietary protein sources can affect energy metabolism.     

Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats

BackgroundThe global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels. We investigate the impact of stimulating portal glucose sensors on systemic glucose levels in health and T2D, and evaluated the role of sodium-glucose-cotransporter-3 (SGLT3) as the possible sensor.MethodsSystemic glucose and hormone responses to portal stimulation were measured. In Sprague-Dawley (SD) rats, post-prandial state was simulated by infusing glucose into the portal vein. The SGLT3 agonist, alpha-methyl-glucopyranoside (αMG), was then added to further stimulate the portal sensor. To elucidate the neural pathway, vagotomy or portal denervation was followed by αMG+glucose co-infusion. The therapeutic potential of portal glucose sensor stimulation was investigated by αMG-only infusion (vs. saline) in SD and Zucker-Diabetic-Fatty (ZDF) rats. Hepatic mRNA expression was also measured.ResultsαMG+glucose co-infusion reduced peak systemic glucose (vs. glucose alone), and lowered hepatic G6Pase expression. Portal denervation, but not vagotomy, abolished this effect. αMG-only infusion lowered systemic glucose levels. This glucose-lowering effect was more pronounced in ZDF rats, where portal αMG infusion increased insulin, C-peptide and GIP levels compared to saline infusions.ConclusionsThe portal vein is capable of sensing its glucose levels, and responds by altering hepatic glucose handling. The enhanced effect in T2D, mediated through increased GIP and insulin, highlights a therapeutic target that could be amenable to pharmacological modulation or minimally-invasive surgery.     

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.     

Effects of gastric bypass surgery on insulin resistance and insulin secretion in nondiabetic obese patients

Roux-en-Y-Gastric-Bypass (RYGB) reduces overall and diabetes-specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time-courses of glucose, insulin, C-peptide, and the incretin glucagon like peptide-1 (GLP-1) following an oral glucose load. Insulin-sensitivity was measured by a hyperinsulinemic-isoglycemic-clamp-test; glucose-turnover was determined using D-[6,6-(2)H(2)] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m(2)) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m(2)), in a lean (CON: BMI: 22.6 ± 0.6 kg/m(2)) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m(2)). RYGB reduced fasting plasma concentrations of insulin and C-peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C-peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic-area under the curve (Dyn-AUC): 0-90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP-1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin-stimulated glucose uptake tended to increase postoperatively (M-value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper-secretion of insulin and C-peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.     

Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1

Dramatic improvement of type 2 diabetes is commonly observed after bariatric surgery. However, the mechanisms behind the alterations in glucose homeostasis are still elusive. We examined the effect of duodenal-jejunal bypass (DJB), which maintains the gastric volume intact while bypassing the entire duodenum and the proximal jejunum, on glycemic control, β-cell mass, islet morphology, and changes in enteroendocrine cell populations in nonobese diabetic Goto-Kakizaki (GK) rats and nondiabetic control Wistar rats. We performed DJB or sham surgery in GK and Wistar rats. Blood glucose levels and glucose tolerance were monitored, and the plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. β-Cell area, islet fibrosis, intestinal morphology, and the density of enteroendocrine cells expressing GLP-1 and/or GIP were quantified. Improved postprandial glycemia was observed from 3 mo after DJB in diabetic GK rats, persisting until 12 mo after surgery. Compared with the sham-GK rats, the DJB-GK rats had an increased β-cell area and a decreased islet fibrosis, increased insulin secretion with increased GLP-1 secretion in response to a mixed meal, and an increased population of cells coexpressing GIP and GLP-1 in the jejunum anastomosed to the stomach. In contrast, DJB impaired glucose tolerance in nondiabetic Wistar rats. In conclusion, although DJB worsens glucose homeostasis in normal nondiabetic Wistar rats, it can prevent long-term aggravation of glucose homeostasis in diabetic GK rats in association with changes in intestinal enteroendocrine cell populations, increased GLP-1 production, and reduced β-cell deterioration.     

The role of the stomach in the control of appetite and the secretion of satiation peptides

It is widely accepted that gastric parameters such as gastric distention provide a direct negative feedback signal to inhibit eating; moreover, gastric and intestinal signals have been reported to synergize to promote satiation. However, there are few human data exploring the potential interaction effects of gastric and intestinal signals in the short-term control of appetite and the secretion of satiation peptides. We performed experiments in healthy subjects receiving either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. Intraduodenal infusions (3 kcal/min) were at rates comparable with the duodenal delivery of these nutrients under physiological conditions. Intraduodenal infusions of glucose elicited only weak effects on appetite and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). In contrast, identical amounts of glucose delivered intragastrically markedly suppressed appetite (P < 0.05) paralleled by greatly increased plasma levels of GLP-1 and PYY (≤3-fold, P < 0.05). Administration of the mixed liquid meal showed a comparable phenomenon. In contrast to GLP-1 and PYY, plasma ghrelin was suppressed to a similar degree with both intragastric and intraduodenal nutrients. Our data confirm that the stomach is an important element in the short-term control of appetite and suggest that gastric and intestinal signals interact to mediate early fullness and satiation potentially by increased GLP-1 and PYY secretions.     

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.     

Adenoviral vector-mediated glucagon-like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that plays an important role in glucose homeostasis. Its functions include glucose-stimulated insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in appetite and food intake. Despite the numerous antidiabetic properties of GLP-1, its therapeutic potential is limited by its short biological half-life due to rapid enzymatic degradation by dipeptidyl peptidase IV. The present study aimed to demonstrate the therapeutic effects of constitutively expressed GLP-1 in an overt type 2 diabetic animal model using an adenoviral vector system. METHODS: A novel plasmid (pAAV-ILGLP-1) and recombinant adenoviral vector (Ad-ILGLP-1) were constructed with the cytomegalovirus promoter and insulin leader sequence followed by GLP-1(7-37) cDNA. RESULTS: The results of an enzyme-linked immunosorbent assay showed significantly elevated levels of GLP-1(7-37) secreted by human embryonic kidney cells transfected with the construct containing the leader sequence. A single intravenous administration of Ad-ILGLP-1 into 12-week-old Zucker diabetic fatty (ZDF) rats, which have overt type 2 diabetes mellitus (T2DM), achieved near normoglycemia for 3 weeks and improved utilization of blood glucose in glucose tolerance tests. Circulating plasma levels of GLP-1 increased in GLP-1-treated ZDF rats, but diminished 21 days after treatment. When compared with controls, Ad-ILGLP-1-treated ZDF rats had a lower homeostasis model assessment for insulin resistance score indicating amelioration in insulin resistance. Immunohistochemical staining showed that cells expressing GLP-1 were found in the livers of GLP-1-treated ZDF rats. CONCLUSIONS: These data suggest that GLP-1 gene therapy can improve glucose homeostasis in fully developed diabetic animal models and may be a promising treatment modality for T2DM in humans.     

Association between 12α-hydroxylated bile acids and hepatic steatosis in rats fed a high-fat diet

High-fat (HF) diet induces hepatic steatosis that is a risk factor for noncommunicable diseases such as obesity, type 2 diabetes and cardiovascular disease. Previously, we found that HF feeding in rats increases the excretion of fecal bile acids (BAs), specifically 12α-hydroxylated (12αOH) BAs. Although the liver is the metabolic center in our body, the association between hepatic steatosis and 12αOH BAs in HF-fed rats is unclear. Thus, we investigated extensively BA composition in HF-fed rats and evaluated the association between hepatic steatosis and 12αOH BAs. Acclimated male inbred WKAH/HkmSlc rats were divided into two groups and fed either control or HF diet for 8 weeks. Feeding HF diet increased hepatic triglyceride and total cholesterol concentrations, which correlated positively with 12αOH BAs concentrations but not with non-12αOH BAs in the feces, portal plasma and liver. Accompanied by the increase in 12αOH BAs, the rats fed HF diet showed increased fat absorption and higher mRNA expression of liver Cidea. The enhancement of 12αOH BA secretion may contribute to hepatic steatosis by the promotion of dietary fat absorption and hepatic Cidea mRNA expression. The increase in 12αOH BAs was associated with enhanced liver cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) mRNA expression. There was a significant increase in 7α-hydroxycholesterol, a precursor of BAs, in the liver of HF-fed rats. Altogether, these data suggest that the HF diet increases preferentially 12αOH BAs synthesis by utilizing the accumulated hepatic cholesterol and enhancing mRNA expression of Cyp7a1 and Cyp8b1 in the liver.     

GLP-1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats

Glucagon-like peptide-1 (GLP-1) influences energy balance by exerting effects on food intake and glucose metabolism, through mechanisms that are partially dependent on the vagal pathway. The aim of this study was to characterize the effects of chronic GLP-1 stimulation on energy homeostasis and glucose metabolism in the absence of vagal innervation Truncal vagotomized (VGX) and sham operated rats (SHAM) received an intraperitoneal GLP-1 infusion (3.5 pmol/kg/min) trough mini-osmotic pumps. To dissect the effects derived from vagal denervation on food intake, an additional group was included consisting of sham operated rats that were PAIR FED to VGX. Food intake and body weight were recorded throughout the experimental period, while the percentage of white and brown adipose tissue, fasting glucose, insulin, gastro-intestinal hormonal profile, hypothalamic, and BAT gene expression were assessed at endpoint. VGX rats had significantly lower food intake, body weight gain, and leptin levels when compared with SHAM rats. Despite having similar body weight, PAIR-FED rats had lower fasting leptin, insulin and insulin resistance, while having higher ghrelin levels than VGX. GLP-1 infusion did not influence food intake or body weight, but was associated with lower leptin levels in VGX and lower pancreatic α-cells ki-67 staining in SHAM. Concluding, this study corroborates that the vagus nerve may modulate whole body energy homeostasis by acting in peripheral signals. Our data suggest that in the absence of vagal or parasympathetic tonus, GLP-1 mediated inhibition of cell proliferation markers in α-cells is prevented, meanwhile leptin suppression, associated with a negative energy balance, is partially overridden.     

Effects of an olive oil-enriched diet on glucagon-like peptide 1 release and intestinal content, plasma insulin concentration, glucose tolerance and pancreatic insulin content in an animal model of type 2 diabetes.

In the light of a recent study conducted in normal rats, the present investigations were aimed at exploring the immediate and long-term effects of an olive oil-enriched diet (OO diet) on GLP-1 release and intestinal content, plasma insulin concentration, glucose tolerance and pancreatic insulin content in adult rats that had been injected with streptozotocin during the neonatal period (STZ rats). The OO diet, when compared to a standard diet, increased the immediate GLP-1 response in meal-trained rats, but decreased GLP-1 content in the intestinal tract after 50 days. Over 50 days, the body weight gain was lower in the rats fed the OO diet compared to standard diet. In the former, however, no improvement of glucose tolerance or insulin response during an oral glucose tolerance test was observed. Thus, a paradoxical lowering of the insulinogenic index, i. e. the paired ratio between plasma insulin and glucose concentration, was recorded during the oral glucose tolerance test in rats fed either standard or OO diet. Moreover, the insulin content of the pancreas was equally low in the STZ rats fed either standard or OO diet. These findings will be discussed in the framework of possible differences in the pathophysiology of B-cell dysfunction in most patients with type-2 diabetes and the present animal model of non-insulin-dependent diabetes.     

Defect in glucokinase translocation in Zucker diabetic fatty rats

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; micromol.kg(-1).min(-1)) were slightly higher in ZDF (8.4 +/- 0.3 and 53 +/- 7, respectively) than in lean rats (6.2 +/- 0.2 and 45 +/- 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 +/- 350) than in lean rats (150 +/- 14). The ratio of hepatic uridine 5'-diphosphate-glucose 3H specific activity to plasma glucose 3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (micromol.kg(-1).min(-1)), and hepatic glucose cycling (micromol.kg(-1).min(-1)) were higher in ZDF (35 +/- 5, 87 +/- 16, and 33 +/- 10, respectively) compared with lean rats (18 +/- 3, 56 +/- 6, and 11 +/- 2, respectively). [3H]glucose incorporation into glycogen (micromol glucose/g liver) was similar in lean (1.0 +/- 0.7) and ZDF (1.6 +/- 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (micromol.kg(-1).min(-1)), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (micromol glucose/g liver) were markedly higher in lean (191 +/- 22, 62 +/- 3, and 5.0 +/- 1.4, respectively) but similar in ZDF rats (100 +/- 6, 37 +/- 3, and 1.4 +/- 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.     

Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB (P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery (P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB (P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time (P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.     

Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1

Bile acids (BAs) are water-soluble end products from cholesterol metabolism and are essential for efficient absorption of dietary lipids. By using targeted somatic mutagenesis of the nuclear receptor liver receptor homolog 1 (LRH-1) in mouse hepatocytes, we demonstrate here that LRH-1 critically regulates the physicochemical properties of BAs. The absence of LRH-1 and subsequent deficiency of Cyp8b1 eliminate the production of cholic acid and its amino acid conjugate taurocholic acid and increase the relative amounts of less amphipathic BA species. Intriguingly, while the expression of Cyp8b1 is almost extinguished in the livers of mice that lack LRH-1, the expression of the rate-limiting enzyme of BA synthesis, i.e., Cyp7a1, remains unchanged. The profound remodeling of the BA composition significantly reduces the efficacy of intestinal absorption of lipids and reuptake of BAs and facilitates the removal of lipids from the body. Our studies unequivocally demonstrate a pivotal role for LRH-1 in determining the composition of BAs, which, in turn has major consequences on whole-body lipid homeostasis.     

Fecal excretion pattern of bile acids in rats fed high fat diets and neomycin in induced colon tumorigenesis.

Neomycin augments colon tumorigenesis in 1,2 - dimethylhydrazine treated rats fed polyunsaturated fat diet and decreases fecal cholic acid excretion, while it inhibits tumorigenesis with increased cholic acid and decreased deoxycholic acid excretions in rats fed high cholesterol diet. Participation of other fecal bile acids seems to be insignificant in relation to colon carcinogenesis.     

An efficient method for the purification and quantification of a galactose-specific lectin from vegetative tissues of Dolichos lablab

The differences among individual bile acids (BAs) in eliciting different physiological and pathological responses are largely unknown because of the lack of valid and simple analytical methods for the quantification of individual BAs and their taurine and glycine conjugates. Therefore, a simple and sensitive LC-MS/MS method for the simultaneous quantification of 6 major BAs, their glycine, and taurine conjugates in mouse liver, bile, plasma, and urine was developed and validated. One-step sample preparation using solid-phase extraction (for bile and urine) or protein precipitation (for plasma and liver) was used to extract BAs. This method is valid and sensitive with a limit of quantification ranging from 10 to 40 ng/ml for the various analytes, has a large dynamic range (2500), and a short run time (20 min). Detailed BA profiles were obtained from mouse liver, plasma, bile, and urine using this method. Muricholic acid (MCA) and cholic acid (CA) taurine conjugates constituted more than 90% of BAs in liver and bile. BA concentrations in liver were about 300-fold higher than in plasma, and about 180-fold higher in bile than in liver. In summary, a reliable and simple LC-MS/MS method to quantify major BAs and their metabolites was developed and applied to quantify BAs in mouse tissues and fluids.