{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:46:04Z","timestamp":1791049564984,"version":"4.1.0"},"reference-count":36,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,12,1]]},"abstract":"<jats:p>Cirrhotic portal hypertension is characterized by increased hepatic oxidative stress, AA (arachidonic acid)-derived TXA2 (thromboxane A2) release and exaggerated hepatic response to the \u03b1-adrenergic agonist MTX (methoxamine). Besides promoting hepatic fibrosis, the role of hyperleptinaemia in the modulation of vascular response in NASH (non-alcoholic steatohepatitis) rat livers remains unknown. The aim of the present study was to explore the possible links between hyperleptinaemia and the disarrangement in the hepatic microcirculation. NASH-cirrhosis with hyperleptinaemia was induced in lean rats by feeding with an HF\/MCD (high-fat\/methionine-choline-deficient) diet. Portal haemodynamics, various substances, protein and mRNA expression and PUFA (polyunsaturated fatty acid) composition were measured. Finally, the effects of leptin pre-infusion on TXA2 release and concentration\u2013PPP (portal perfusion pressure) curves in response to MTX were evaluated by simultaneously pre-treatment with the Kupffer cell inactivators GdCl3 (gadolinium chloride) or EC (encapsulated clodronate), the TXS (TXA2 synthase) inhibitor furegrelate, the TP receptor (TXA2 receptor) antagonist SQ29548 and the dual TXS\/TP receptor antagonist BM567. In HF\/MCD+leptin-lean rats, cirrhosis-induced PPP and MTX hyper-responsiveness were associated with increased hepatic TXA2 production, TBARS (thiobarbituric acid-reacting substances) levels and the AA (arachidonic acid)\/n\u22123 PUFA ratio, and up-regulation of hepatic leptin, FAS (fatty acid synthase), NADPH oxidase subunits, TXS, TP receptor, TGF\u03b21 (transforming growth factor \u03b21) proteins and mRNAs. Pre-infusion of leptin significantly enhanced MTX-stimulated PPP elevation and TXA2 release, which were attenuated by GdCl3 and EC pre-treatment. Concomitantly pre-incubation with BM567, but not furegrelate or SQ29548, significantly abolished the leptin-enhanced MTX-stimulated increase in PPP in NASH-cirrhotic rats. Hyperleptinaemia plays an important role in hyper-responsiveness to MTX in NASH-cirrhotic rat livers with portal hypertension. The leptin-enhanced MTX-stimulated increase in PPP is mediated by increased oxidative stress and Kupffer-cell-activated AA-derived TXA2 release in NASH-cirrhotic rats.<\/jats:p>","DOI":"10.1042\/cs20110572","type":"journal-article","created":{"date-parts":[[2012,6,28]],"date-time":"2012-06-28T08:25:32Z","timestamp":1340871932000},"page":"669-680","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Kupffer cell depletion attenuates leptin-mediated methoxamine-stimulated portal perfusion pressure and thromboxane A2 release in a rodent model of NASH-cirrhosis"],"prefix":"10.1042","volume":"123","author":[{"given":"Ying-Ying","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Tsau","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"},{"name":"National Research Institute of Chinese Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Hu","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Institute of Traditional Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chih","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa-Yauh","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Dong","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Chieh","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2012,8,10]]},"reference":[{"key":"2021113010213337400_B1","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/sj.ijo.0800768","article-title":"An increase of circulating leptin in patients with liver cirrhosis","volume":"22","author":"Shimizu","year":"1998","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"2021113010213337400_B2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/hep.23998","article-title":"Osteopontin is induced by Hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis","volume":"53","author":"Syn","year":"2011","journal-title":"Hepatology"},{"key":"2021113010213337400_B3","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1053\/gast.2002.32995","article-title":"Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat","volume":"122","author":"Ikejima","year":"2002","journal-title":"Gastroenterology"},{"key":"2021113010213337400_B4","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/sj.ijo.0801209","article-title":"Development of a high fat diet-induced obesity and leptin resistance in C57B2\/6J mice","volume":"24","author":"Lin","year":"2000","journal-title":"Int. J. Obes."},{"key":"2021113010213337400_B5","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1055\/s-2002-38264","article-title":"Effects of fatty (fa) allele and high fat diet on adipose tissue leptin and lipid metabolism","volume":"34","author":"Heo","year":"2002","journal-title":"Horm. Metab. Res."},{"key":"2021113010213337400_B6","doi-asserted-by":"crossref","first-page":"H816","DOI":"10.1152\/ajpheart.00695.2001","article-title":"Augmented vasoconstriction in hypertensive diabetic obese Zucker rats","volume":"282","author":"Stepp","year":"2002","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"2021113010213337400_B7","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1002\/hep.21874","article-title":"Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet","volume":"46","author":"Matsuzawa","year":"2007","journal-title":"Hepatology"},{"key":"2021113010213337400_B8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1161\/01.HYP.0000198555.51645.f1","article-title":"Leptin regulates cardiomyocyte contractile function through endothelin-1 receptor-NADPH oxidase pathway","volume":"47","author":"Dong","year":"2006","journal-title":"Hypertension"},{"key":"2021113010213337400_B9","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/hep.22166","article-title":"Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability","volume":"47","author":"Garcia-Sancho","year":"2008","journal-title":"Hepatology"},{"key":"2021113010213337400_B10","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1165\/rcmb.2002-0033OC","article-title":"Oxidative stress induces arachidonate release from human lung cells through the epithelial factor receptor pathway","volume":"27","author":"Pawliczak","year":"2002","journal-title":"Am. J. Respir. Mol. Biol."},{"key":"2021113010213337400_B11","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.bbalip.2006.03.014","article-title":"Oxidative stress and arachidonic acid mobilization","volume":"1761","author":"Balboa","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"2021113010213337400_B12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S1098-8823(03)00080-7","article-title":"Eicosanoids in cirrhosis and portal hypertension","volume":"73","author":"Birney","year":"2003","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"2021113010213337400_B13","doi-asserted-by":"crossref","first-page":"G453","DOI":"10.1152\/ajpgi.00315.2002","article-title":"Role of thromboxane A2 in early BDL-induced portal hypertension","volume":"284","author":"Yokoyama","year":"2003","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"2021113010213337400_B14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1053\/jhep.2003.50004","article-title":"Cycloxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat liver","volume":"37","author":"Graupera","year":"2003","journal-title":"Hepatology"},{"key":"2021113010213337400_B15","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1096\/fj.04-2291fje","article-title":"A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats","volume":"19","author":"Carmiel-Haggai","year":"2005","journal-title":"FASEB. J."},{"key":"2021113010213337400_B16","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jhep.2003.09.020","article-title":"The methionine-choline deficient dietary model of steatohepatitis dose not exhibit insulin resistance","volume":"40","author":"Rinella","year":"2004","journal-title":"J. Hepatol."},{"key":"2021113010213337400_B17","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jhep.2010.09.026","article-title":"The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension","volume":"54","author":"Lin","year":"2011","journal-title":"J. Hepatol."},{"key":"2021113010213337400_B18","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/hep.21626","article-title":"Omega-3 fatty acids alleviate chemically induced acute hepatitis by suppression of cytokines","volume":"45","author":"Schm\u00f6cker","year":"2007","journal-title":"Hepatology"},{"key":"2021113010213337400_B19","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1172\/JCI119532","article-title":"Receptor mediated regional sympathetic nerve activation by leptin","volume":"100","author":"Haynes","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2021113010213337400_B20","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1161\/01.HYP.30.3.619","article-title":"Sympathetic and cardiorenal actions of leptin","volume":"30","author":"Haynes","year":"1997","journal-title":"Hypertension"},{"key":"2021113010213337400_B21","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1002\/hep.510230544","article-title":"Kupffer cell depletion by liposome-delivered drugs: comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid","volume":"23","author":"Rooijen","year":"1996","journal-title":"Hepatology"},{"key":"2021113010213337400_B22","doi-asserted-by":"crossref","first-page":"L497","DOI":"10.1152\/ajplung.00010.2004","article-title":"Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing groups IVC iPLA2 (cPLA2\u03b3) protein expression","volume":"287","author":"Mancuso","year":"2004","journal-title":"Am. J. Physiol. Lung. Cell. Mol. Physiol."},{"key":"2021113010213337400_B23","doi-asserted-by":"crossref","first-page":"220\u2013227","DOI":"10.1016\/j.jhep.2007.03.014","article-title":"Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers","volume":"47","author":"Gracia-Sancho","year":"2007","journal-title":"J. Hepatol."},{"key":"2021113010213337400_B24","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1152\/japplphysiol.01337.2004","article-title":"Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets","volume":"99","author":"Fike","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"2021113010213337400_B25","doi-asserted-by":"crossref","first-page":"R154","DOI":"10.1152\/ajpregu.00245.2005","article-title":"Enhanced role for Rho-A-associated kinase in adrenergic-mediated vasoconstriction in gracilis arteries from obese Zucker rat","volume":"290","author":"Naik","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2021113010213337400_B26","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1053\/j.gastro.2006.10.014","article-title":"Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis","volume":"132","author":"Ota","year":"2007","journal-title":"Gastroenterology"},{"key":"2021113010213337400_B27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0303-7207(02)00007-2","article-title":"Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in\u00a0vitro","volume":"190","author":"Bruun","year":"2002","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021113010213337400_B28","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1097\/HJH.0b013e32833c21af","article-title":"Is leptin involved in phagocytic NADPH oxidase overactivity in obesity? Potential clinical implications","volume":"28","author":"Fortuno","year":"2010","journal-title":"J. Hypertens."},{"key":"2021113010213337400_B29","doi-asserted-by":"crossref","first-page":"25096","DOI":"10.1074\/jbc.M007383200","article-title":"Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A","volume":"276","author":"Yamagishi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021113010213337400_B30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0968-0004(93)90051-N","article-title":"The biochemical basis of the NADPH oxidase of phagocytes","volume":"18","author":"Segal","year":"1993","journal-title":"Trends Biochem. Sci."},{"key":"2021113010213337400_B31","first-page":"472","article-title":"Regulation of oxidative stress and inflammation by hepatic adiponectin receptor 1\u00a0in an animal model of nonalcoholic steatohepatitis","volume":"3","author":"Matsunami","year":"2010","journal-title":"In. J. Clin. Exp. Pathol."},{"key":"2021113010213337400_B32","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1023\/A:1007019510569","article-title":"Activity of the leukocyte NADPH oxidase in whole neutrophils and cell-free neutrophil preparations stimulated with long-chain polyunsaturated fatty acids","volume":"25","author":"Schneider","year":"2011","journal-title":"Inflammation"},{"key":"2021113010213337400_B33","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and its critical in hepatic fibrosis","volume":"112","author":"Baraller","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2021113010213337400_B34","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1053\/gast.2002.31040","article-title":"5\u2013Lipoxygenase inhibitor reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes","volume":"22","author":"Graupera","year":"2002","journal-title":"Gastroenterology"},{"key":"2021113010213337400_B35","doi-asserted-by":"crossref","first-page":"G328","DOI":"10.1152\/ajpgi.00367.2005","article-title":"Roles of anandamide in the hepatic microcirculation in cirrhotic rats","volume":"290","author":"Yang","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"2021113010213337400_B36","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1097\/SHK.0b013e3181b85934","article-title":"Kupffer cell activation by hydrogen peroxide: a new mechanism of portal pressure increase","volume":"33","author":"Steib","year":"2010","journal-title":"Shock"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/123\/12\/669\/442971\/cs1230669.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/123\/12\/669\/442971\/cs1230669.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T10:45:38Z","timestamp":1638269138000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/123\/12\/669\/68985\/Kupffer-cell-depletion-attenuates-leptin-mediated"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,10]]},"references-count":36,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2012,12,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20110572","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,10]]}}}