Gastric Load Research Articles

Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells

Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.

Fermented milk containing Lactobacillus paracasei and Glycyrrhiza glabra has a beneficial effect in patients with Helicobacter pylori infection: A randomized, double-blind, placebo-controlled study.

Background:Lactobacillus paracasei and Glycyrrhiza glabra have been reported as having beneficial effects on Helicobacter pylori infection. We aimed to assess the efficacy and safety of fermented milk containing L paracasei HP7 and G glabra in patients with H pylori infection.Methods:This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted in 2 hospitals from April to December 2017. Patients with H pylori infection were randomized into either the treatment group (fermented milk with L paracasei HP7 and G glabra) or placebo group (fermented milk only) once daily for 8 weeks. The primary endpoint was the gastric load of H pylori measured by 13C-urea breath test (UBT). Secondary endpoints were histologic and clinical improvement.Results:A total of 142 patients were randomly allocated to the treatment (n = 71) or placebo groups (n = 71). Compared to baseline data, the quantitative value of 13C-UBT at 8 weeks was significantly reduced in the treatment group (from 20.8 ± 13.2% to 16.9 ± 10.8%, P = .035), but not in the placebo group (P = .130). Chronic inflammation improved significantly only in the treatment group (P = .013), whereas the neutrophil activity deteriorated significantly only in the placebo group (P = .003). Moreover, the treatment group had significant improvement in gastrointestinal symptoms (P = .049) and quality of life (P = .029). No serious adverse events were observed.Conclusion:The combination of fermented milk containing L paracasei and G glabra reduced H pylori density and improved histologic inflammation. However, their mechanisms of action should be elucidated in further studies.

Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital.

BackgroundHelicobacter pylori infection increases risk for gastric cancer. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA. Colonization density may also influence disease and cagA has been associated with higher shedding in stool. However, the relationship between H. pylori load in the stool and in the stomach is not clear.MethodsTo investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China.ResultsQuantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fisher’s Exact Test, p = 0.03).ConclusionH. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk.ImpactThis study contributes to our understanding of H. pylori dynamics in the context of pathological changes.

Effects of Oral Exposure Duration and Gastric Energy Content on Appetite Ratings and Energy Intake in Lean Men.

Studies show that longer oral exposure to food leads to earlier satiation and lowers energy intake. Moreover, higher energy content of food has been shown to lead to higher satiety. Up to now, it has not been studied systematically how oral exposure duration and gastric energy content interact in satiety regulation. Thirty-seven men (22 ± 4 years, 22 ± 2 kg/m2) participated in a randomized cross-over trial, in which we independently manipulated: (1) oral exposure duration by modified sham feeding (MSF) for 1 or 8 min; and (2) energy content of gastric load (GL) by a nasogastric tube: 100 kcal/500 mL or 700 kcal/500 mL. Outcome measures were appetite ratings and subsequent energy intake from an ad libitum meal. Energy intake was 35% lower after the GLs with 700 kcal than with 100kcal (p < 0.0001). All appetite ratings were lower in the 700 kcal than in the 100 kcal treatments (area under the curve (AUC); p-values ≤ 0.002); fullness was higher and prospective consumption was lower in the 8 min than in the 1 min MSF treatments (AUC; p-values ≤ 0.02). In conclusion, the current showed that a GL of 700 kcal/500 mL vs. 100 kcal/500 mL increased satiety and lowered energy intake. No additional effects of oral exposure duration could be observed, presumably due to the high contrast in energy between the manipulations. Future research should also focus on the role of oral exposure as such and not only the duration.

Longer Oral Exposure with Modified Sham Feeding Does Not Slow Down Gastric Emptying of Low- and High-Energy-Dense Gastric Loads in Healthy Young Men1–3

Background: A long oral exposure to food and a high-energy density of food have been shown to increase satiety feelings. The effect of energy density is predominantly caused by an inhibition of gastric emptying. It is hypothesized that prolonging oral exposure may have an additional effect on this inhibition of gastric emptying. However, little human data are available to support this hypothesis.Objective: The objective was to assess the effect of the duration of oral exposure to food on gastric emptying rate of gastric loads (GLs) low and high in energy density and on satiety feelings.Methods: Twenty-six healthy men [mean ± SD age: 22 ± 3 y; BMI (in kg/m2): 23 ± 1] participated in a randomized crossover trial with 4 treatments and a control. Treatments consisted of either 1- or 8-min modified sham feeding (MSF) of cake, and a GL of either 100 or 700 kcal infused in the stomach via a nasogastric tube (500 mL, 62.5 mL/min). The control consisted of no MSF and a GL of 500 mL of water. Gastric emptying rate was assessed with a 13C breath test. Breath samples and satiety feelings were collected at fixed time points until 90 min after start of the treatment.Results: Gastric emptying rate and satiety feelings were not affected by duration of MSF (P ≥ 0.27). However, the 700-kcal GL treatments slowed gastric emptying [41% lower area under the curve (AUC)] and increased satiety feelings (22–31% higher AUC) compared with the 100-kcal GL treatments (P < 0.001). No interaction between MSF duration and energy density of GL was found (P ≥ 0.44).Conclusions: Higher gastric energy density inhibited gastric emptying and increased satiety feelings in healthy young men. However, prolonging oral exposure to food did not have an additional effect. This study provides more insight in satiety regulation. This trial was registered at trialregister.nl as NTR3601.

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic β-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive β-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

Taste Hedonics Influence the Disposition of Fat by Modulating Gastric Emptying in Rats

We investigated how preferred and nonpreferred tastes influence the disposition of fat. Adult male Sprague Dawley rats were infused with 5 ml of 20% intralipid through an intragastric catheter and with 0.3 ml of a taste solution through an intraoral catheter. At 120 min postinfusion, plasma concentrations of fat fuels (triglycerides and non-esterified fatty acids) were either unchanged or slightly higher after rats tasted a preferred sweet taste solution (0.125% saccharin +3% glucose) than after they tasted water. They were markedly lower after rats tasted a non-preferred solution–either a bitter solution (0.15% quinine hydrochloride) or a sweet solution that had previously been the conditioned stimulus for lithium-induced taste aversion. The distribution of 14C-triolein mixed with the gastric load was determined at 4 h postinfusion. Rats that received a non-preferred bitter taste had significantly more 14C remaining in the stomach than did those that received a preferred sweet taste. These results suggest that taste hedonics–either unconditioned or conditioned aversive tastes–influence fat disposition by altering gastric emptying.

Sensitivity and specificity of hypnosis effects on gastric myoelectrical activity.

ObjectivesThe effects of hypnosis on physiological (gastrointestinal) functions are incompletely understood, and it is unknown whether they are hypnosis-specific and gut-specific, or simply unspecific effects of relaxation.DesignSixty-two healthy female volunteers were randomly assigned to either a single session of hypnotic suggestion of ingesting an appetizing meal and an unappetizing meal, or to relax and concentrate on having an appetizing or unappetizing meal, while the electrogastrogram (EGG) was recorded. At the end of the session, participants drank water until they felt full, in order to detect EGG-signal changes after ingestion of a true gastric load. During both conditions participants reported their subjective well-being, hunger and disgust at several time points. ResultsImagining eating food induced subjective feelings of hunger and disgust as well as changes in the EGG similar to, but more pronounced than those seen with a real gastric water load during both hypnosis and relaxation conditions. These effects were more pronounced when imagining an appetizing meal than with an unappetizing meal. There was no significant difference between the hypnosis and relaxation conditions. ConclusionImagination with and without hypnosis exhibits similar changes in subjective and objective measures in response to imagining an appetizing and an unappetizing food, indicating high sensitivity but low specificity.

Contribution of Secretory Antibodies to Intestinal Mucosal Immunity against Helicobacter pylori

The natural immune response to Helicobacter pylori neither clears infection nor prevents reinfection. However, the ability of secretory antibodies to influence the course of H. pylori infection has not been determined. We compared the natural progression of H. pylori infection in wild-type C57BL/6 mice with that in mice lacking the polymeric immunoglobulin receptor (pIgR) that is essential for the secretion of polymeric antibody across mucosal surfaces. H. pylori SS1-infected wild-type and pIgR knockout (KO) mice were sampled longitudinally for gastrointestinal bacterial load, antibody response, and histological changes. The gastric bacterial loads of wild-type and pIgR KO mice remained constant and comparable at up to 3 months postinfection (mpi) despite SS1-reactive secretory IgA in the intestinal contents of wild-type mice at that time. Conversely, abundant duodenal colonization of pIgR KO animals contrasted with the near-total eradication of H. pylori from the intestine of wild-type animals by 3 mpi. H. pylori was cultured only from the duodenum of those animals in which colonization in the distal gastric antrum was of sufficient density for immunohistological detection. By 6 mpi, the gastric load of H. pylori in wild-type mice was significantly lower than in pIgR KO animals. While there was no corresponding difference between the two mouse strains in gastric pathology results at 6 mpi, reductions in gastric bacterial load correlated with increased gastric inflammation together with an intestinal secretory antibody response in wild-type mice. Together, these results suggest that naturally produced secretory antibodies can modulate the progress of H. pylori infection, particularly in the duodenum.

Effect of GutGard in the Management ofHelicobacter pylori: A Randomized Double Blind Placebo Controlled Study

A randomized, double blind placebo controlled study was conducted to evaluate the efficacy of GutGard (root extract of Glycyrrhiza glabra) in the management of Helicobacter pylori (H. pylori) gastric load. Participants diagnosed with H. pylori infection were randomly assigned to two groups to orally receive 150 mg of GutGard (n = 55) or placebo (n = 52) once daily for 60 days. H. pylori infection was assessed using 13C-urea breath test (13C-UBT) at days 0, 30, and 60. Stool Antigen test (HpSA) was also performed on days 0, 30, and 60. Repeated measures of analysis of variance (RMANOVA), chi-square, and Fisher's exact probability tests were used to compare the treatment outcomes. A significant interaction effect between group and time (P = 0.00) and significant difference in mean Delta Over Baseline (DOB) values between GutGard (n = 50) and placebo (n = 50) treated groups after intervention period were observed. On day 60, the results of HpSA test were negative in 28 subjects (56%) in GutGard treated group whereas in placebo treated group only 2 subjects (4%) showed negative response; the difference between the groups was statistically significant. On day 60, the results of 13C-UBT were negative in 24 (48%) in GutGard treated group and the difference between the groups was statistically significant. The findings suggest GutGard is effective in the management of H. pylori.

Decreased intestinal nutrient response in diet-induced obese rats: role of gut peptides and nutrient receptors

Diet-induced obesity (DIO) is an excellent model for examining human obesity comprising both genotypic and environmental (diet) factors. Decreased responsiveness to peripheral satiety signaling may be responsible for the hyperphagia in this model. In this study, we investigated responses to nutrient-induced satiation in outbred DIO and DIO-resistant (DR) rats fed a high-energy/high-fat (HE/HF) diet as well as intestinal satiety peptide content, intestinal nutrient-responsive receptor abundance and vagal anorectic receptor expression. Outbred DIO and DR rats fed a HE/HF diet were tested for short-term feeding responses following nutrient (glucose and intralipid (IL)) gastric loads. Gene and protein expressions of intestinal satiety peptides and fatty acid-responsive receptors were examined from isolated proximal intestinal epithelial cells and cholecystokinin-1 receptor (CCK-1R) and leptin receptor (LepR) mRNA from the nodose ganglia of DIO and DR animals. DIO rats were less responsive to IL- (P<0.05) but not glucose-induced suppression of food intake compared with DR rats. DIO rats exhibited decreased CCK, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1; P<0.05 for each) protein expression compared with DR rats. Also, DIO rats expressed more G-protein-coupled receptor 40 (GPR40; P<0.0001), GPR41 (P<0.001) and GPR120 (P<0.01) relative to DR rats. Finally, there were no differences in mRNA expression for CCK-1R and LepR in the nodose ganglia of DIO and DR rats. Development of DIO may be partly due to decreased fat-induced satiation through low levels of endogenous satiety peptides, and changes in intestinal nutrient receptors.

The First Evidence of Hereditary and Familial Gastric Cancer in Latvia: Implications for Prevention

Gastric cancer is a frequent cause of cancer mortality. The prognosis of established tumor is unfavorable due to the propensity to spread and limited treatment efficiency. Therefore, prevention has a high significance. We tested a population screening approach in order to identify families with an increased gastric cancer load for further surveillance. Population screening was performed by questionnaire reaching 76.6% of the population. Hereditary gastric cancer (HGC) syndrome was diagnosed if 3 mutually first-degree relatives with gastric cancer were reported in the kindred. Additional group (HGC2) of families with 2 first-degree relatives affected by gastric cancer was identified. The HGC syndrome was diagnosed in 0.11%, but HGC2 syndrome, in 0.4% probands. The gastric cancer frequency among blood relatives was 25.2% (95% CI, 20.6%-30.4%) in HGC, but 16.0% (95% CI, 13.8%-18.5%) in HGC2 families. The mean age at diagnosis of cancer was 56.9 years (95% CI, 53.4-60.3) in HGC and 62.5 years (95% CI, 60.1-64.8) in HGC2. The mean survival was 2.6 years (95% CI, 1.2-4.0). Population screening identifies reasonable number of families with a high frequency of gastric cancer. The frequency of gastric cancer and an unfavorable course characterized by low survival justify surveillance in families with 2 or 3 first-degree relatives affected by gastric cancer. Population screening provides the age characteristics of the respective tumors in order to adjust the surveillance schedule.

Feeding responses to gastric nutrient loads in diet-induced obese and resistant rats

Feeding responses to gastric nutrient loads in diet-induced obese and resistant rats

Hormonal and Psychological Factors Linked to the Increased Thermic Effect of Food in Malnourished Fasting Anorexia Nervosa

In patients with anorexia nervosa (AN), weight gain is lower than that expected from the energy content of the meals. Thus we investigated the thermic effect of food (TEF) in relation to subjective feelings and plasma hormone levels in a group of AN patients. TEF, feelings (14 items), and plasma release of beta-endorphin, ACTH, cortisol, dopamine, and catecholamines were evaluated in 15 AN patients (body mass index, 13.6 +/- 1.2 kg.m(-2)) and in 15 healthy women after three gastric loads (0, 300, 700 kcal) infused by a nasogastric tube in a blind design. In AN, the blind loads induced an energy-dependent increase in TEF (P < 0.001), which was higher than that observed in healthy women (P < 0.001). Only in AN, a load-dependent decline in the high basal plasma level of beta-endorphin (P < 0.01), an increase in plasma ACTH (P < 0.02) after the two caloric loads, and an increase in cortisol, norepinephrine, and dopamine levels after the 700-kcal load only (P < 0.05) were noted. A calorie-dependent (P < 0.001) increase in nausea, abdominal discomfort, and fear of being fat ratings and a decrease in liking to eat (P < 0.001) and body image were observed in AN patients (P < 0.05). TEF correlated with ratings on satiation, nausea, uncomfortable abdominal swelling, body image, and fear of being fat (for all, P < 0.01). In AN women, blindly infused loads induced a dose-dependent increase in TEF, which correlated with the increase in plasma cortisol, ACTH, and catecholamines as in unpleasant sensations, fear of being fat, and anxiety as well as a decline in elevated basal beta-endorphin. These results could explain the difficulty for AN patients in gaining weight.

Gut Vagal Afferents Are Not Necessary for the Eating-Stimulatory Effect of Intraperitoneally Injected Ghrelin in the Rat

Ghrelin is unique among gut peptides in that its plasma level increases during fasts and its administration stimulates eating. Although ghrelin physiology has been intensively studied, whether its eating-stimulatory effect arises from endocrine-neural signal transduction at peripheral or central sites remains unresolved. To address this issue, we tested the effects of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method available, on ghrelin-induced eating. SDA was verified with a cholecystokinin satiation test, retrograde labeling of vagal motor neurons in the dorsal motor nucleus of the vagus with fluorogold, and anterograde labeling of vagal afferents in the nucleus tractus solitarius with wheat germ agglutinin-horseradish peroxidase. Intraperitoneal injections of 10-40 microg/kg ghrelin stimulated eating as robustly in rats with verified complete SDA as in sham-operated controls. Ghrelin also stimulated eating in rats with total subdiaphragmatic vagotomies. We also recorded the electrophysiological responses of gastric load-sensitive vagal afferent neurons to intravenous ghrelin. Ghrelin (10 nmol) phasically (0-30 s) increased activity in two of seven gastric load-sensitive fibers in the absence of gastric loads and tonically (5-30 min) increased activity in only one fiber. Ghrelin did not affect any of the eight fibers tested in the presence of 1-3 ml gastric loads. We conclude that although phasic increases in plasma ghrelin may affect the activity of a fraction of gastric load-sensitive vagal afferents, the acute eating-stimulatory effect of intraperitoneal ghrelin does not require vagal afferent signaling.

Hunger and satiety: one brain for two?

understanding the physiological controls of eating and developing effective pharmacological tools to reduce eating has never been more important. The modern world faces an unprecedented obesity epidemic, and the current treatment strategies are rather unsuccessful. One possible solution may be a

Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

our understanding of the controls of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually

Serotonin type-3 receptors mediate cholecystokinin-induced satiation through gastric distension

We have previously shown that serotonin type-3 (5-HT3) receptors mediate cholecystokinin (CCK)-induced satiation and that this effect is dependent on postoropharyngeal feedback. However, the independent contributions of gastric and intestinal feedback in 5-HT3 receptor mediation of suppression of food intake by CCK have not been determined. Using a sham-feeding preparation combined with intraduodenal sucrose infusion, we show that blockade of 5-HT3 receptors by ondansetron (1 mg/kg ip) had no effect on suppression of sham feeding by intraduodenal 15% sucrose infusion (4 ml/10 min), CCK (2 microg/kg ip) administration, or the combination of the two treatments. In separate experiments consisting of either sham-feeding rats that received gastric distension with the use of a balloon or real-feeding rats whose stomachs were distended using gastric loads of saline after the occlusion of the pylorus, we tested the hypothesis that gastric feedback signals are necessary for activation of 5-HT3 receptors. Ondansetron significantly attenuated suppression of sham sucrose intake after a 10-ml gastric balloon distension (30.5 +/- 2.2 vs. 20.2 +/- 2.2 ml, respectively) and gastric distension combined with CCK (21.9 +/- 1.4 vs. 12.0 +/- 1.7 ml, respectively). When intestinal feedback was eliminated in a real-feeding paradigm by closing the pylorus using a cuff preparation, ondansetron attenuated suppression of sucrose intake produced by a 10-ml saline gastric load (6.8 +/- 0.7 vs. 4.2 +/- 0.4 ml, respectively). Finally, when CCK (1 microg/kg) was administered in combination with a 5-ml saline gastric load in a real-feeding preparation, ondansetron significantly attenuated suppression of sucrose intake by CCK (9.0 +/- 0.9 vs. 6.3 +/- 0.5 ml, respectively), as well as the enhanced suppression of intake by CCK plus gastric load (6.9 +/- 0.6 vs. 4.6 +/- 0.5 ml, respectively). These findings demonstrate that CCK-induced activation of 5-HT3 receptors requires gastric, but not intestinal feedback.

Inhibition of Transient Lower Esophageal Sphincter Relaxation and Gastroesophageal Reflux by Metabotropic Glutamate Receptor Ligands

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal acid reflux. TLESR is mediated via vagal pathways, which may be modulated by metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1 and 5) have excitatory effects on neurons, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) are inhibitory. This study determined the effect of mGluRs on triggering of TLESR and reflux in an established conscious ferret model. Esophageal manometric/pH studies were performed in ferrets with chronic esophagostomies. TLESR were induced by a gastric load of 25 mL glucose (pH 3.5) and 30 mL air. In control treated animals, gastric load induced 3.52 +/- 0.46 TLESRs per 47-minute study, 89.7% of which were associated with reflux episodes (n = 16). The mGluR5 antagonist MPEP inhibited TLESR dose dependently, with maximal 71% +/- 7% inhibition at 35 micromol/kg (n = 9; P < .0001). MPEP also significantly reduced reflux episodes (P < .001) and increased basal lower esophageal sphincter pressure (P < .05). MPEP inhibited swallowing dose dependently, suggesting a common action on trigger mechanisms for swallowing and TLESR. The more selective analogue, MTEP, had more potent effects (90% +/- 6% inhibition TLESR at 40 micromol/kg; n = 8; P < .0001). In contrast, the group I agonist DHPG tended to increase TLESR. The group II agonist (2R, 4R)-APDC was ineffective, whereas the group III agonist L-(AP4 slightly reduced TLESR (33% at 11 micromol/kg; P < .05). The selective mGluR8 agonist (S)-3, 4-DCPG inhibited TLESR by 54% at 15 micromol/kg (P < .01). mGluR5 antagonists potently inhibit TLESR and reflux in ferrets, implicating mGluR5 in the mechanism of TLESR. mGluR5 antagonists are therefore promising as therapy for patients with GERD.

Knockdown of Hepatic ABCA1 by RNA Interference Decreases Plasma HDL Cholesterol Levels and Influences Postprandial Lipemia in Mice

To investigate the impact of hepatic ABCA1 on systemic lipoprotein metabolism in vivo by an adenovirus-mediated RNA interference approach. Efficiency of plasmid-based small interference RNA (siRNA)-induced knockdown of cotransfected murine ATP binding cassette transporter A1 (mABCA1) in HEK-293 cells was judged by RT-polymerase chain reaction, immunofluorescence, and Western blot analysis. The most effective plasmid was used to generate a recombinant adenovirus as a tool to selectively downregulate ABCA1 expression in mouse liver (C57BL/6). In comparison to controls, Western blot analysis from liver membrane proteins of Ad-anti-ABCA1 infected mice resulted in an approximately 50% reduction of endogenous ABCA1 and a clear upregulation of apolipoprotein E. Fast protein liquid chromatography analysis of plasma revealed that hepatic ABCA1 protein reduction was associated with an approximately 40% decrease of HDL cholesterol and a reduction of HDL-associated apolipoprotein A-I and E. In the fasted state, other lipoprotein classes were not affected. To analyze the influence of ABCA1 downregulation on postprandial lipemia, infected mice were given a gastric load of radiolabeled trioleate in olive oil. In Ad-anti-ABCA1 infected mice, the postprandial increase of chylomicrons and chylomicron-associated apolipoproteins B and E was significantly reduced as compared with controls. Hepatic ABCA1 contributes to HDL plasma levels and influences postprandial lipemia.