AJP - Gastrointestinal and Liver Physiology

Yao, Lihang; Dawson, Paul A.; Woollett, Laura A.

doi: 10.1152/ajpgi.00332.2002pmid: 12529268

Abstract Gallstones develop when the secretion of cholesterol is elevated compared with the secretion of bile acids into bile. One of the risk factors for the formation of gallstones is pregnancy. Because the pregnancy-induced increase in hepatic cholesterol synthesis rates could play a critical role in the development of cholesterol stones, the aim of the present study was to determine whether stone formation, as assessed by the ratio of cholesterol to bile acids in bile, could be ablated by blocking the pregnancy-induced increase in hepatic sterol synthesis rates. Golden Syrian hamsters were fed either ground chow or chow supplemented with 0.5% cholesterol for 3 wk and studied in the nonpregnant state or in late gestation. In chow-fed animals, a 1.6-fold increase in the ratio of cholesterol to bile acids occurred simultaneously with a sevenfold increase in hepatic sterol synthesis rate and a ninefold increase in the amount of newly synthesized cholesterol secreted into the bile in late gestation. In the cholesterol-fed dams, an increase in the ratio of cholesterol to bile acids occurred even with the lack of induction of hepatic sterol synthesis rates during pregnancy. Thus it appears that the marked induction of hepatic sterol synthesis rates during gestation is not essential for the pregnancy-induced cholesterol saturation of bile when cholesterol is fed to animals. gallstones gestation Footnotes This work was supported by National Institutes of Health Grants HD-34089 (to L. A. Woollett), P01 DK-54504 (to L. A. Woollett), HL-49373 (to P. A. Dawson), and DK-47987 (to P. A. Dawson). Dr. Woollett was an Established Investigator of the American Heart Association while this study was performed. Address for reprint requests and other correspondence: L. A. Woollett, Dept. of Pathology, Univ. of Cincinnati, Cincinnati, Ohio 45267-0529 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpgi.00332.2002 Copyright © 2003 the American Physiological Society

Percy, W. H.; Fromm, T. H.; Wangsness, C. E.

doi: 10.1152/ajpgi.00179.2002pmid: 12388209

Abstract This in vitro study tested the hypothesis that muscularis mucosae contractile activity contributes to rabbit colonic mucosal function by mechanisms other than simple mechanical deformation of the epithelium. Experiments were performed by using a technique that allows simultaneous recording of muscle activity and transmucosal potential difference, a measure of epithelial ion transport. ATP, bradykinin, histamine, PGE 2 , PGF 1α , and PGF 2α elicited muscularis mucosae contractions that were resistant to atropine and TTX. Only ATP-induced contractions were indomethacin sensitive, and only those to dimethylphenylpiperazinium iodide (DMPP) were reduced by atropine. All agonist-evoked increases in transmucosal potential difference were atropine resistant, and, with the exception of those to PGE 2 , PGF 2α , and VIP, they were also TTX sensitive. Mucosal responses to ATP, bradykinin, and histamine were indomethacin sensitive, whereas those to DMPP, the prostaglandins, and VIP were not. When cyclooxygenase activity or the mucosal innervation was compromised, even maximal muscularis mucosae contractions did not produce large secretory responses. It is concluded that contraction-related prostaglandin synthesis and noncholinergic secretomotor neuron stimulation represent the physiological transduction mechanism through which muscularis mucosae motor activity is translated into mucosal secretion. motility mucosa submucosal plexus transduction pathway integrated function rabbit Footnotes Address for reprint requests and other correspondence: W. H. Percy, Division of Basic Biomedical Sciences, School of Medicine, The Univ. of South Dakota, Vermillion, SD 57069-2390 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 16, 2002;10.1152/ajpgi.00179.2002 Copyright © 2003 the American Physiological Society

Murthy, Karnam S.; Zhou, Huiping

doi: 10.1152/ajpgi.00401.2002pmid: 12529267

Abstract This study examined the expression of inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) types and PKG isoforms in isolated gastric smooth muscle cells and determined the ability of PKG and PKA to phosphorylate IP 3 Rs and inhibit IP 3 -dependent Ca 2+ release, which mediates the initial phase of agonist-induced contraction. PKG-Iα and PKG-Iβ were expressed in gastric smooth muscle cells, together with IP 3 -R-associated cG-kinase substrate, a protein that couples PKG-Iβ to IP 3 R-I. IP 3 R-I and IP 3 R-III were also expressed, but only IP 3 R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Iα in vitro showed that PKA phosphorylated the same site as PKG (presumably S 1755 ) and an additional PKA-specific site (S 1589 ). In intact muscle cells, agents that activated PKG or both PKG and PKA induced IP 3 R-I phosphorylation that was reversed by the PKG inhibitor (8R,9S,11s)-(−)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,1H,-2,7b,11a-trizadizo-benzo9(a,g)cycloocta(c,d,e)-trinden-1-one. Agents that activated PKA induced IP 3 R-I phosphorylation in permeabilized but not intact muscle cells, implying that PKA does not gain access to IP 3 R-I in intact muscle cells. The pattern of IP 3 R-I phosphorylation in vivo and in vitro was more consistent with phosphorylation by PKG-Iα. Phosphorylation of IP 3 R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP 3 -induced Ca 2+ release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. We conclude that IP 3 R-I is selectively phosphorylated by PKG-I in intact smooth muscle resulting in inhibition of IP 3 -dependent Ca 2+ release. relaxation gastric muscle calcium release Footnotes Address for reprint requests and other correspondence: K. S. Murthy, P.O. Box 980711, Medical College of Virginia, Virginia Commonwealth Univ., Richmond, VA 23298 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpgi.00401.2002 Copyright © 2003 the American Physiological Society

Pouderoux, Philippe; Verdier, Eric; Kahrilas, Peter J.

doi: 10.1152/ajpgi.00301.2002pmid: 12388187

Abstract Lower esophageal sphincter (LES) relaxation and esophageal body inhibition co-occur during esophageal peristalsis but not necessarily during pharyngeal stimulation or transient LES relaxation (tLESR). This study examined these relationships and the impact on reflux. Nine young volunteers were studied. An artificial high-pressure zone (HPZ) was established, and pH was recorded 8 and 5 cm proximal to the LES. Pharyngeal stimulation was by water injection and gastric distension with liquid or gas. Peristalsis, pharyngeal stimulation, and spontaneous events were recorded. Swallowing relaxed the LES in 100% of trials (the HPZ in 80%) and caused no reflux. Pharyngeal stimulation relaxed the LES in two-thirds of trials, had no effect on the HPZ, and caused no reflux. Gastric distension was associated with 117 tLESRs, 48% with acid reflux, and 32% with gas reflux; there was no effect on the HPZ. We conclude that LES relaxation is a necessary but not sufficient condition for reflux. LES relaxation and esophageal body inhibition are independent events that may be concurrent (swallowing) or dissociated (tLESR). esophageal primary peristalsis transient LES relaxation gastroesophageal reflux pharynx swallow Footnotes Address for reprint requests and other correspondence: P. Pouderoux, Service d'Hépato-Gastroentérologie et Alcoologie, Centre Hospitalier et Universitaire de Nı̂mes, Hôpital Caremeau, Ave. du Professeur Robert Debré, 30900 Nı̂mes, France (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 15, 2002;10.1152/ajpgi.00301.2002 Copyright © 2003 the American Physiological Society

Wolkoff, Allan W.; Cohen, David E.

doi: 10.1152/ajpgi.00409.2002pmid: 12529265

Abstract Bile acids are cholesterol derivatives that serve as detergents in bile and the small intestine. Approximately 95% of bile acids secreted by hepatocytes into bile are absorbed from the distal ileum into the portal venous system. Extraction from the portal circulation by the hepatocyte followed by reexcretion into the bile canaliculus completes the enterohepatic circulation of these compounds. Over the past few years, candidate bile acid transport proteins of the sinusoidal and canalicular plasma membranes of the hepatocyte have been identified. The physiology of hepatocyte bile acid transport and its relationship to these transport proteins is the subject of this Themes article. organic anion transporting protein Na + -taurocholate cotransporting polypeptide bile salt export pump Footnotes Address for reprint requests and other correspondence: A. W. Wolkoff, Marion Bessin Liver Research Center, 625 Ullmann Bldg., Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (E-mail: [email protected] ). 10.1152/ajpgi.00409.2002 Copyright © 2003 the American Physiological Society

Nanji, Amin A.; Jokelainen, Kalle; Tipoe, George L.; Rahemtulla, Amir; Thomas, Peter; Dannenberg, Andrew J.

doi: 10.1152/ajpgi.00230.2002pmid: 12388178

Abstract Induction of NF-κB-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease (ALD). Curcumin, a phenolic antioxidant, inhibits the activation of NF-κB. We determined whether treatment with curcumin would prevent experimental ALD and elucidated the underlying mechanism. Four groups of rats (6 rats/group) were treated by intragastric infusion for 4 wk. One group received fish oil plus ethanol (FE); a second group received fish oil plus dextrose (FD). The third and fourth groups received FE or FD supplemented with 75 mg · kg −1 · day −1 of curcumin. Liver samples were analyzed for histopathology, lipid peroxidation, NF-κB binding, TNF-α, IL-12, monocyte chemotactic protein-1, macrophage inflammatory protein-2, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitrotyrosine. Rats fed FE developed fatty liver, necrosis, and inflammation, which was accompanied by activation of NF-κB and the induction of cytokines, chemokines, COX-2, iNOS, and nitrotyrosine formation. Treatment with curcumin prevented both the pathological and biochemical changes induced by alcohol. Because endotoxin and the Kupffer cell are implicated in the pathogenesis of ALD, we investigated whether curcumin suppressed the stimulatory effects of endotoxin in isolated Kupffer cells. Curcumin blocked endotoxin-mediated activation of NF-κB and suppressed the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells. Thus curcumin prevents experimental ALD, in part by suppressing induction of NF-κB-dependent genes. antioxidants cyclooxygenase nitric oxide Footnotes This study was supported by grants from the Research Grants Council of Hong Kong and National Institutes of Health. Dr. Kalle Jokelainen was supported by grants from the Academy of Finland, Finnish Cultural Foundation, and Yrjö Jahnsson Foundation. Address for reprint requests and other correspondence: A. A. Nanji, Dept. of Pathology and Laboratory Medicine, Univ. of Pennsylvania School of Medicine, 7.046 Founders Pavilion, 3400 Spruce St., Philadelphia, PA 19104-4283 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published August 28, 2002;10.1152/ajpgi.00230.2002 Copyright © 2003 the American Physiological Society

Blum, Arthur M.; Metwali, Ahmed; Elliott, David E.; Weinstock, Joel V.

doi: 10.1152/ajpgi.00271.2002pmid: 12388184

Abstract Substance P (SP) enhances antigen-dependent T cell IFN-γ production. It was determined if a T cell neurokinin-1 receptor (NK-1R) was critical for IFN-γ regulation. T cells from schistosome-infected mice were mixed with splenocytes from uninfected NK-1R knockout (KO) animals. Thus only the schistosome egg antigen-specific T cells expressed NK-1R. The cells were cultured 18 h with or without SP. SP enhanced antigen-induced IFN-γ production fourfold without affecting IL-4 or IL-5 secretion. NK-1R inhibitor blocked this stimulation. Neither purified T cells nor naı̈ve KO splenocytes cultured alone responded to antigen. To further define the importance of T cell NK-1R, we developed a T cell-selective NK-1R KO mouse by reconstituting T cell-deficient Rag mice with NK-1R KO T cells. These mice challanged with schistosomiasis developed abnormal liver granulomas. Granuloma size was smaller in T cell-selective NK-1R KO mice compared with granulomas in Rag reconstituted with normal T cells. Splenocytes and granuloma cells from NK-1R KO mice made less IFN-γ. The mice also made less IgG2a. Thus T cell NK-1R is important for IFN-γ regulation. neuropeptides inflammation granuloma neurokinin 1 receptor schistosomiasis Footnotes Address for reprint requests and other correspondence: J. V. Weinstock, Div. of Gastroenterology (4607 JCP), Univ. of Iowa Hospital and Clinics, 200 Hawkins Dr., Iowa City, IA 52242–1009 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 2, 2002;10.1152/ajpgi.00271.2002 Copyright © 2003 the American Physiological Society

Marucci, Luca; Alpini, Gianfranco; Glaser, Shannon S.; Alvaro, Domenico; Benedetti, Antonio; Francis, Heather; Phinizy, Jo Lynne; Marzioni, Marco; Mauldin, Jeremy; Venter, Julie; Baumann, Brandy; Ugili, Laura; LeSage, Gene

doi: 10.1152/ajpgi.00245.2002pmid: 12388182

Abstract Bile acids are cytoprotective in hepatocytes by activating phosphatidylinositol-3-kinase (PI3-K) and its downstream signal AKT. Our aim was to determine whether feeding taurocholate to CCl 4 -treated rats reduces cholangiocyte apoptosis and whether this cytoprotective effect is dependent on PI3-K. Cholangiocyte proliferation, secretion, and apoptosis were determined in cholangiocytes from bile duct ligation (BDL), CCl 4 -treated BDL rats, and CCl 4 -treated taurocholate-fed rats. In vitro, we tested whether CCl 4 induces apoptosis and whether loss of cholangiocyte proliferation and secretion is dependent on PI3-K. The CCl 4 -induced cholangiocyte apoptosis and loss of cholangiocyte proliferation and secretion were reduced in CCl 4 -treated rats fed taurocholate. CCl 4 -induced cholangiocyte apoptosis, loss of cholangiocytes secretion, and proliferation were prevented by preincubation with taurocholate. Taurocholate cytoprotective effects were ablated by wortmannin. Taurocholate prevented, in vitro, CCl 4 -induced decrease of phosphorylated AKT protein expression in cholangiocytes. The cytoprotective effects of taurocholate on CCl 4 effects on cholangiocyte proliferation and secretion were abolished by wortmannin. Taurocholate protects cholangiocytes from CCl 4 -induced apoptosis by a PI3-K-dependent mechanism. Bile acids are important in the prevention of drug-induced ductopenia in cholangiopathies. cytoprotection biliary epithelium bile acids Footnotes ↵ * L. Marucci and G. Alpini share the first authorship. Address for reprint requests and other correspondence: G. LeSage, Professor of Medicine, Univ. of Texas Houston Medical School, 6431 Fannin St., MSB 4.234, Houston TX 77030 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 2, 2002;10.1152/ajpgi.00245.2002 Copyright © 2003 the American Physiological Society

Rich, Adam; Miller, Steven M.; Gibbons, Simon J.; Malysz, John; Szurszewski, Joseph H.; Farrugia, G.

doi: 10.1152/ajpgi.00093.2002pmid: 12388202

Abstract The binding of Steel factor (SF) to c-kit initiates a signaling pathway essential for development and maintenance of interstitial cells of Cajal (ICC). Soluble and membrane-bound isoforms of SF are expressed in the gastrointestinal tract, but the role for either isoform in supporting ICC development is unknown. The aim of this study was to determine the role of SF in supporting ICC in culture. ICC were cultured from dissociated mouse jejunum and grown with fibroblast cell lines that produced either soluble, membrane-bound or membrane-restricted SF. ICC were identified and counted by c-kit immunoreactivity. The number of c-kit immunoreactive cells was greater in the coculture system compared with cultures grown without SF-producing fibroblasts. All forms of SF-producing fibroblasts increased ICC number in culture but physical separation of the fibroblasts from the c-kit immunoreactive cells, the addition of exogenous SF to the culture medium, or fibroblast-conditioned media did not. These results are consistent with the hypothesis that the membrane-bound form of SF preferentially contributes to expression of c-kit-positive ICC under cell culture conditions. immunocytochemistry gastrointestinal pacemaker Steel-factor proteolysis Footnotes This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-57061, DK-52766, and DK-17238. Address for reprint requests and other correspondence: A. Rich, Bristol-Myers Squibb, Bldg. 21, Rm. 1318, 311 Rockyhill-Pennington Road, Pennington, NJ 08534 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 9, 2002;10.1152/ajpgi.00093.2002 Copyright © 2003 the American Physiological Society

Boyd, K. A.; O'Donovan, D. G.; Doran, S.; Wishart, J.; Chapman, I. M.; Horowitz, M.; Feinle, C.

doi: 10.1152/ajpgi.00375.2002pmid: 12409281

Abstract There is evidence that gastrointestinal function adapts in response to a high-fat (HF) diet. This study investigated the hypothesis that an HF diet modifies the acute effects of duodenal lipid on appetite, antropyloroduodenal pressures, plasma CCK and plasma glucagon-like peptide-1 (GLP-1) levels in humans. Twelve healthy men were studied twice in randomized, crossover fashion. The effects of a 90-min duodenal lipid infusion (6.3 kJ/min) on the above parameters were assessed immediately following 14-day periods on either an HF or a low-fat (LF) diet. After the HF diet, pyloric tonic and phasic pressures were attenuated, and the number of antropyloroduodenal pressure-wave sequences was increased when compared with the LF diet. Plasma CCK and GLP-1 levels did not differ between the two diets. Hunger was greater during the lipid infusion following the HF diet, but there was no difference in food intake. Therefore, exposure to an HF diet for 14 days attenuates the effects of duodenal lipid on antropyloroduodenal pressures and hunger without affecting food intake or plasma hormone levels. antropyloroduodenal pressures cholecystokinin glucose-like peptide-1 energy intake Footnotes Dr. Feinle is supported by a Florey Research Fellowship from the Royal Adelaide Hospital. Address for reprint requests and other correspondence: C. Feinle, Univ. of Adelaide Dept. of Medicine, Eleanor Harrald Bldg., Level 6, Royal Adelaide Hospital, Adelaide, SA 5000 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published October 30, 2002;10.1152/ajpgi.00375.2002 Copyright © 2003 the American Physiological Society