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- Title
Kupffer cell depletion attenuates leptin-mediated methoxamine-stimulated portal perfusion pressure and thromboxane A<sub>2</sub> release in a rodent model of NASH-cirrhosis.
- Authors
YANG, Ying-Ying; HUANG, Yi-Tsau; TSAI, Tung-Hu; HOU, Ming-Chih; LEE, Fa-Yauh; LEE, Shou-Dong; LIN, Han-Chieh
- Abstract
Cirrhotic portal hypertension is characterized by increased hepatic oxidative stress, AA (arachidonic acid)-derived TXA2 (thromboxane A2) release and exaggerated hepatic response to the a-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 hepaticmicrocirculation. NASH-cirrhosis with hyperleptinaemia was induced in lean rats by feeding with an HF/MCD (high-fat/methioninecholine- 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-PPP (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-3 PUFA ratio, and up-regulation of hepatic leptin, FAS (fatty acid synthase), NADPH oxidase subunits, TXS, TP receptor, TGFß1 (transforming growth factor ß1) 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.
- Subjects
KUPFFER cells; LEPTIN; ARACHIDONIC acid; ALPHA adrenoceptors; PERFUSION; THROMBOXANES; LABORATORY rodents; PORTAL hypertension; CIRRHOSIS of the liver; FATTY liver
- Publication
Clinical Science, 2012, Vol 123, Issue 12, p669
- ISSN
0143-5221
- Publication type
Article
- DOI
10.1042/CS20110572