title: High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.
abstract: In patients with cirrhosis, endotoxic shock is a major complication of portal hypertension, which is related partly to intrahepatic endothelial nitric oxide synthase (eNOS) down-regulation. High-density lipoproteins (HDLs), whose plasma levels are reduced in cirrhosis, have an anti-inflammatory effect by neutralizing circulating lipopolysaccharide (LPS), and they increase eNOS activity in endothelial cells. Therefore, the aim of this study was to assess the effects of reconstituted high-density lipoprotein (rHDL) administration on the LPS-induced proinflammatory response, intrahepatic eNOS regulation, and portal hypertension in cirrhotic rats. Cirrhotic and control rats were pretreated with rHDL or saline and challenged with LPS or saline. The neutralization of LPS in HDL was assessed by the measurement of HDL-bound fluorescent LPS levels. Plasma tumor necrosis factor alpha (TNFalpha) and lipopolysaccharide binding protein (LBP) levels were measured. The expression of hepatic TNFalpha, LBP, inducible nitric oxide synthase (iNOS), and caveolin-1 (a major eNOS inhibitor) and the activity of protein kinase B (Akt; a major eNOS activator) and eNOS were determined. The portal pressure was measured. The plasma HDL levels were significantly lower in cirrhotic rats than in control rats. In cirrhotic rats, the plasma levels of HDL-bound fluorescent LPS were 50% lower than those in controls, and they were restored after rHDL administration. The plasma TNFalpha levels were significantly higher in LPS-challenged cirrhotic rats than in controls and significantly decreased after rHDL administration. rHDL administration decreased hepatic TNFalpha, LBP, iNOS, and caveolin-1 expression, restored hepatic eNOS and Akt activity, and significantly lowered the portal pressure and intrahepatic vascular resistance.
  
  
  CONCLUSIONS
  In cirrhotic rats, rHDL administration decreases the hepatic proinflammatory signals induced by LPS, restores the hepatic eNOS activity, and lowers the portal pressure. This suggests that the decrease in circulating HDL in cirrhosis plays a role in the excessive proinflammatory response and intrahepatic eNOS down-regulation.
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Paris 75018, France. dthabut@libertysurf.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Tazi
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnefont-Rousselot
authors.forename: Maria
authors.initials: M
authors.lastname: Aller
authors.forename: Olivier
authors.initials: O
authors.lastname: Farges
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Guimont
authors.forename: Zera
authors.initials: Z
authors.lastname: Tellier
authors.forename: Cecile
authors.initials: C
authors.lastname: Guichard
authors.forename: Eric
authors.initials: E
authors.lastname: Ogier-Denis
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: Didier
authors.initials: D
authors.lastname: Lebrec
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D008075:Lipoproteins, HDL / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000276:immunology*; D008107:Liver Diseases / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017082:Portal Pressure / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008075:Lipoproteins, HDL; D019001:Nitric Oxide Synthase