Hepatic endothelin‐1 and endocannabinoids‐dependent effects of hyperleptinemia in nonalcoholic steatohepatitis‐cirrhotic rats

摘要: Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic cirrhotic livers. Leptin brain an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) characterized by hyperleptinemia. This study explores possible mechanisms of hyperleptinemia relation to increased intrahepatic resistance (IHR) portal hypertension NASH rats. rats with were induced Zucker (fa/fa) lean feeding animals high fat/methionine-choline-deficient (HF/MCD) diet without exogenous administration recombinant leptin. Portal venous pressure (PVP), IHR, plasma hepatic levels various substances, histopathology liver, hydroxyproline content, expression messenger RNA (mRNA) measured. Hepatic microcirculatory dysfunction vasoconstrictive response endothelin-1 also observed using liver perfusion system intravital microscopy. Finally, leptin stellate cells (HSCs) was evaluated. Both HF/MCD-Zucker HF/MCD+leptin rats, significant fibrogenesis cirrhosis, marked hypertension, dysfunction, enhanced endothelin-1, IHR found be associated higher endocannabinoids, cannabinoid type 1 receptor, A receptor (ETAR), activator protein-1, transforming growth factor beta (TGF-β)1, osteopontin, tumor necrosis alpha (TNF-α), leptin, (OBRb). Interestingly, acute incubation directly increases ETAR, OBRb protein-1 HSCs. Conclusion: An HF/MCD increase endocannabinoids production, promote fibrogenesis, enhance aggravate dysfunction; these events subsequently (HEPATOLOGY 2012)