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In Vitro and In Vivo Protection of Stellate Cells from Apoptosis by Leptin

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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 α-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 α-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.

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Acknowledgements

This work was supported by a KO8 award (K08DK002965), the Yale Liver Center (NIH P 30 DK34989), a Yale Liver Center Training Grant (NIH T32 DK07356), and a Pilot Project grant from the Yale Liver Center. There are no competing interests and no sponsors, and approval was obtained for all animal experiments.

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Authors and Affiliations

  1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, 06520, USA

    Amir Qamar, Shehzad Zafar Sheikh, Muhammad Nauman Jhandier, Irteza Bin Inayat, Wyel Hakim & Wajahat Zafar Mehal

  2. Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA

    Ali Masud & Wajahat Zafar Mehal

  3. Section of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, 06520, USA

    Ali Masud

  4. Section of Digestive Diseases, Yale University, 333 Cedar Street, 1080 LMP, New Haven, Connecticut, 06520-8019, USA

    Wajahat Zafar Mehal

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  1. Amir Qamar
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  2. Shehzad Zafar Sheikh
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  3. Ali Masud
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  4. Muhammad Nauman Jhandier
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  7. Wajahat Zafar Mehal
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Correspondence to Wajahat Zafar Mehal.

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Qamar, A., Sheikh, S.Z., Masud, A. et al. In Vitro and In Vivo Protection of Stellate Cells from Apoptosis by Leptin. Dig Dis Sci 51, 1697–1705 (2006). https://doi.org/10.1007/s10620-006-9244-8

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  • DOI: https://doi.org/10.1007/s10620-006-9244-8

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