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Lack of Fas antagonism by Met in human fatty liver disease

Nature Medicine volume 13, pages 1078–1085 (2007)Cite this article

Abstract

Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor–mediated pathways, particularly that of Fas-FasL, causing hepatic injury that can eventually proceed to cirrhosis and end-stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met α-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

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Figure 1: Met is dissociated from Fas in fatty liver disease.
Figure 2: Dissociation of Met from Fas in hepatocytes is cell autonomous and is triggered by free fatty acids.
Figure 3: The α-chain of Met (AlphaMet) interacts with Fas via a YLGA amino acid motif located near the N-terminal tail of the Met α-chain.
Figure 4: Synthetic AlphaMet and YLGA-containing peptide block Fas-mediated apoptosis and liver damage in mice.
Figure 5: YLGA 12-mer therapy blocks liver damage in ob/ob (Lep−/−) mice.
Figure 6: YLGA peptide inhibited hepatocyte apoptotic activity, inflammatory infiltration and liver fibrosis in mice given an MCD diet.

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Acknowledgements

We thank M. Lenardo and R. Siegel (US National Institutes of Health) for providing us with CFP and YFP-tagged Fas expression vectors, and C. Dai and X. He for their assistance. This work was supported by an R01 grant from National Institutes of Health (R01CA095782) awarded to R.Z.

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, University of Pittsburgh, S411A Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, 15261, Pennsylvania, USA

    Chunbin Zou, Jihong Ma, Xue Wang, Lida Guo, Zhenqi Zhu, John Stoops, Amanda E Eaker, Carla J Johnson, Stephen Strom, George K Michalopoulos, Marie C DeFrances & Reza Zarnegar

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  1. Chunbin Zou
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Contributions

C.Z. performed most of the experimental work, in particular mapping of the Fas binding site on Met and its anti-apoptotic characterization using in vitro and in vivo models, and also prepared the figures and helped with manuscript writing. J.M., X.W. and Z.Z. contributed to the assessment of Met-Fas complex formation in human fatty liver. L.G. established Met knockdown by siRNA in HepG2 cells. J.S. and A.E.E. performed most aspects of the animal studies, including peptide injection and tissue collection. C.J.J. performed the in vitro studies of YLGA peptide effects on Met activation by HGF and Met signaling in Hepa1-6 cells. S.S. collected human liver specimens and prepared primary cultures of human hepatocytes. G.K.M. provided primary cultures of mouse hepatocytes and also offered invaluable discussion. M.C.D. contributed critically to the histological evaluation of liver tissues, oversaw the BIAcore experiments and assisted with results interpretation. R.Z. formulated the hypothesis that Fas antagonism by Met may be deranged in fatty liver disease, designed nearly all of the experimental procedures and finalized the manuscript.

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Correspondence to Reza Zarnegar.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–7 and Supplementary Methods (PDF 2004 kb)

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Zou, C., Ma, J., Wang, X. et al. Lack of Fas antagonism by Met in human fatty liver disease. Nat Med 13, 1078–1085 (2007). https://doi.org/10.1038/nm1625

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