title: Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD.
abstract: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, CIBERrehd, University of Barcelona, Barcelona, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Pasarín
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Mura
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Héctor
authors.initials: H
authors.lastname: García-Calderó
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
mesh_terms: D000818:Animals; D004032:Diet / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000473:pathology*; D005234:Fatty Liver / Q000150:complications / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D006439:Hemodynamics; D007249:Inflammation / Q000150:complications; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008833:Microcirculation; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation