Kupffer cell depletion attenuates leptin-mediated methoxamine-stimulated portal perfusion pressure and thromboxane A2 release in a rodent model of NASH-cirrhosis.
Cirrhotic portal hypertension is characterized by increased hepatic oxidative stress, AA (arachidonic acid)-derived TXA(2) (thromboxane A(2)) release and exaggerated hepatic response to the α-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 TXA(2) release and concentration-PPP (portal perfusion pressure) curves in response to MTX were evaluated by simultaneously pre-treatment with the Kupffer cell inactivators GdCl(3) (gadolinium chloride) or EC (encapsulated clodronate), the TXS (TXA(2) synthase) inhibitor furegrelate, the TP receptor (TXA(2) 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 TXA(2) 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, TGFβ(1) (transforming growth factor β(1)) proteins and mRNAs. Pre-infusion of leptin significantly enhanced MTX-stimulated PPP elevation and TXA(2) release, which were attenuated by GdCl(3) 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 TXA(2) release in NASH-cirrhotic rats.
Department of Medicine, Taipei Veterans General Hospital, Taiwan. yyyang@vghtpe.gov.tw
Ying-Ying
YY
Yang
Yi-Tsau
YT
Huang
Tung-Hu
TH
Tsai
Ming-Chih
MC
Hou
Fa-Yauh
FY
Lee
Shou-Dong
SD
Lee
Han-Chieh
HC
Lin
D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology; D002794:Choline / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D059305:Diet, High-Fat; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005682:Gadolinium / Q000494:pharmacology; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000209:etiology / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D008715:Methionine / Q000172:deficiency; D008729:Methoxamine / Q000378:metabolism*; D008833:Microcirculation / Q000502:physiology; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism*
C434802:BM 567; D001572:Benzofurans; D017931:DNA Primers; D005231:Fatty Acids, Unsaturated; D020738:Leptin; D012333:RNA, Messenger; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds; D017392:Thiobarbituric Acid Reactive Substances; D004002:Clodronic Acid; D016718:Arachidonic Acid; D013928:Thromboxane A2; D008715:Methionine; D005682:Gadolinium; D008729:Methoxamine; C039936:furegrelate; D002794:Choline; C038958:gadolinium chloride