title: Hepatic endothelin-1 and endocannabinoids-dependent effects of hyperleptinemia in nonalcoholic steatohepatitis-cirrhotic rats.
abstract: Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET(A) R), activator protein-1, transforming growth factor beta (TGF-β)(1), osteopontin, tumor necrosis factor alpha (TNF-α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET(A) R, OBRb and activator protein-1 in HSCs.
  
  
  CONCLUSIONS
  An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats.
authors.affiliation: Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. yangyy@vghtpe.gov.tw
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.forename: Yi-Tsau
authors.initials: YT
authors.lastname: Huang
authors.forename: Tzung-Yan
authors.initials: TY
authors.lastname: Lee
authors.forename: Che-Chang
authors.initials: CC
authors.lastname: Chan
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D001835:Body Weight; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D063388:Endocannabinoids; D019332:Endothelin-1 / Q000378:metabolism*; D005234:Fatty Liver / Q000150:complications / Q000503:physiopathology*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006975:Hypertension, Portal / Q000150:complications / Q000503:physiopathology*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology; D007728:Kupffer Cells / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008833:Microcirculation; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D018709:Statistics, Nonparametric
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D019332:Endothelin-1; D020738:Leptin; D012333:RNA, Messenger