title: In vitro and in vivo protection of stellate cells from apoptosis by leptin.
abstract: Hepatic fibrogenesis is reduced in the absence of leptin. We hypothesized that leptin protects hepatic stellate cells (HSCs) from apoptosis and tested this in in vitro and in vivo systems. (i) Fas ligand (fas-L)-mediated apoptosis was induced in vitro in activated HSCs in the absence and presence of leptin. (ii) HSC apoptosis was also induced by UV irradiation in the absence and presence of leptin. (iii) Fas-L-mediated apoptosis was induced in vitro in HSCs from db/db mice in the absence and presence of leptin. (iv) Liver fibrosis was induced in wt and db/db mice. (v) Liver fibrosis was induced in wild-type mice with TAA, and mice received additional leptin or a control solution. HSC apoptosis was assessed by TUNEL staining. Western blot for alpha-SMA was used to determine differences in HSC activation. Results were as follows. (i) Fas-L induced significant apoptosis of HSC, and preincubation with leptin reduced this approximately threefold. (ii) Leptin provided no protection from UV-induced apoptosis. (iii) HSCs from db/db mice were not protected by leptin against fas-L-induced apoptosis. (iv) TAA-induced fibrosis was significantly less in db/db mice compared to wild type. (v) Wild-type mice receiving leptin had less apoptosis and more alpha-SMA than controls. We conclude that leptin protects HSC from in vitro and in vivo apoptosis. The antiapoptotic effect of leptin requires the long form of the leptin receptor and interacts with the apoptotic pathway proximal to mitochondrial activation.
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Qamar
authors.forename: Shehzad Zafar
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Ali
authors.initials: A
authors.lastname: Masud
authors.forename: Muhammad Nauman
authors.initials: MN
authors.lastname: Jhandier
authors.forename: Irteza Bin
authors.initials: IB
authors.lastname: Inayat
authors.forename: Wyel
authors.initials: W
authors.lastname: Hakim
authors.forename: Wajahat Zafar
authors.initials: WZ
authors.lastname: Mehal
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D053222:Fas Ligand Protein; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D013853:Thioacetamide
chemical_list: D000199:Actins; D053222:Fas Ligand Protein; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D013853:Thioacetamide; C515447:leptin receptor, mouse; C498862:Acta2 protein, rat