title: The role of leptin in progression of non-alcoholic fatty liver disease.
abstract: Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the role of leptin in fibrogenesis in the liver. Xenobiotics-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, an inborn leptin- and leptin receptor (Ob-R)-deficient animal, respectively. Further, leptin increased transforming growth factor (TGF)-beta mRNA in isolated sinusoidal endothelial cells and Kupffer cells, suggesting that leptin promotes hepatic fibrogenesis through up-regulation of TGF-beta in the liver. Moreover, leptin augmented PDGF-dependent proliferation of HSCs by enhancing downstream intracellular signaling pathways via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/Akt. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. These findings indicate that leptin is one of the key regulators for inflammation and progression of fibrosis in various chronic liver diseases including NASH.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okumura
authors.forename: Tie
authors.initials: T
authors.lastname: Lang
authors.forename: Hajime
authors.initials: H
authors.lastname: Honda
authors.forename: Wataru
authors.initials: W
authors.lastname: Abe
authors.forename: Shunhei
authors.initials: S
authors.lastname: Yamashina
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sato