Advertisement

Linking of Senescence to Autophagy Deficiency in Chronic Liver Disease

Open AccessPublished:May 20, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.04.010
      Cellular senescence is a state of irreversible cell-cycle arrest while cells still maintain metabolic activity. Senescence generally is activated as an adaptive response to stresses, such as oxidative stress, oncogene activation, and DNA damage. Morphologically, senescent cells have an enlarged size and flattened morphology with nuclear accumulation of senescence-associated heterochromatic foci and senescence-associated DNA damage foci. Although there are no universal biomarkers for senescence, senescent cells generally have increased β-galactosidase activity; increased cell-cycle inhibitory proteins; such as p21/CDKN1A, p16/CDKN2A, and TP53; as well as increased secretion of a variety of factors, collectively termed as senescence-associated secretory phenotype (SASP).
      • Aravinthan A.D.
      • Alexander G.J.M.
      Senescence in chronic liver disease: Is the future in aging?.
      Autophagy is a catabolic pathway in which the cellular contents are wrapped in the double-membrane autophagosomes and delivered to lysosomes for degradation.
      • Qian H.
      • Chao X.
      • Williams J.
      • Fulte S.
      • Li T.
      • Yang L.
      • Ding W.X.
      Autophagy in liver diseases: A review.
      Interestingly, stresses such as oxidative stress and DNA damage that trigger senescence also can activate autophagy or apoptosis. It is conceivable that the magnitude of the stresses may decide a cell should undergo autophagy, senescence, or apoptosis. Although both senescence and autophagy have been implicated in chronic liver diseases,
      • Aravinthan A.D.
      • Alexander G.J.M.
      Senescence in chronic liver disease: Is the future in aging?.
      ,
      • Qian H.
      • Chao X.
      • Williams J.
      • Fulte S.
      • Li T.
      • Yang L.
      • Ding W.X.
      Autophagy in liver diseases: A review.
      the inter-relationship of autophagy and senescence in liver pathogenesis of autophagy-defective livers has not been studied.
      Mice with genetic deletion of autophagy-related genes, such as Atg5 or Atg7, develop liver injury, inflammation, fibrosis, and spontaneous adenoma.
      • Ni H.M.
      • Woolbright B.L.
      • Williams J.
      • Copple B.
      • Cui W.
      • Luyendyk J.P.
      • Jaeschke H.
      • Ding W.X.
      Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
      ,
      • Khambu B.
      • Huda N.
      • Chen X.
      • Antoine D.J.
      • Li Y.
      • Dai G.
      • Köhler U.A.
      • Zong W.X.
      • Waguri S.
      • Werner S.
      • Oury T.D.
      • Dong Z.
      • Yin X.M.
      HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.
      In this issue of Cellular and Molecular Gastroenterology and Hepatology, Huda et al
      • Huda N.
      • Khambu B.
      • Liu G.
      • Nakatsumi H.
      • Yan S.
      • Chen X.
      • Ma M.
      • Dong Z.
      • Nakayama K.I.
      • Yin X.M.
      Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.
      investigated the temporal changes, possible mechanisms, and role of senescence in the pathogenesis of mouse livers with defective hepatic autophagy. They found that senescence markers, including β-galactosidase activity, p15/Cdkn2b, p21/Cdkn1a, and Cdkn3, as well as senescence-associated DNA damage, senescence-associated heterochromatic foci, and SASP, all were increased in liver-specific Atg7 knockout (L-Atg7 KO) mice in an age-dependent manner. Because L-Atg5 or L-Atg7 KO mice develop liver injury at 2 months old,
      • Ni H.M.
      • Woolbright B.L.
      • Williams J.
      • Copple B.
      • Cui W.
      • Luyendyk J.P.
      • Jaeschke H.
      • Ding W.X.
      Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
      ,
      • Khambu B.
      • Huda N.
      • Chen X.
      • Antoine D.J.
      • Li Y.
      • Dai G.
      • Köhler U.A.
      • Zong W.X.
      • Waguri S.
      • Werner S.
      • Oury T.D.
      • Dong Z.
      • Yin X.M.
      HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.
      ,
      • Ni H.M.
      • Chao X.
      • Yang H.
      • Deng F.
      • Wang S.
      • Bai Q.
      • Qian H.
      • Cui W.
      • Shi Y.
      • Zong W.X.
      • Wang Z.
      • Yang L.
      • Ding W.X.
      Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver.
      senescence could be secondary to hepatocyte damage. However, using an elegant tamoxifen-inducible Atg7 deletion approach in adult mice, Huda et al
      • Huda N.
      • Khambu B.
      • Liu G.
      • Nakatsumi H.
      • Yan S.
      • Chen X.
      • Ma M.
      • Dong Z.
      • Nakayama K.I.
      • Yin X.M.
      Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.
      showed that some of the senescent markers were increased as early as day 5 after deletion of Atg7, suggesting that senescence could be triggered independently of hepatocyte damage in the absence of autophagy.
      Mechanistic studies have shown that increased expression of chemokines in autophagy-defective livers likely was owing to the activation of forkhead box K1 transcription factor, but not the activation of nuclear factor-κB and GATA4, 2 well-known transcription factors that are associated with senescence and SASP.
      • Acosta J.C.
      • O'Loghlen A.
      • Banito A.
      • Guijarro M.V.
      • Augert A.
      • Raguz S.
      • Fumagalli M.
      • Da Costa M.
      • Brown C.
      • Popov N.
      • Takatsu Y.
      • Melamed J.
      • d'Adda di Fagagna F.
      • Bernard D.
      • Hernando E.
      • Gil J.
      Chemokine signaling via the CXCR2 receptor reinforces senescence.
      Furthermore, using isolated hepatocytes and nonparenchymal cells from L-Atg7 KO mouse livers, Huda et al
      • Huda N.
      • Khambu B.
      • Liu G.
      • Nakatsumi H.
      • Yan S.
      • Chen X.
      • Ma M.
      • Dong Z.
      • Nakayama K.I.
      • Yin X.M.
      Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.
      found that hepatocytes, but not nonparenchymal cells, were the primary source for increased chemokine production. Autophagy-deficient livers have increased inflammation, as shown by increased F4/80 or CD11b-positive macrophages, which likely is mediated by chemokine (C-C motif) ligand 2 (CCL2) family chemokines. Indeed, deletion of Ccr2 attenuated hepatocyte senescence and SASP, suggesting C-C chemokine receptor type 2 (CCR2)-mediated signaling may form a feedback loop between senescent hepatocytes and SASP in autophagy-deficient livers. CCR2 was more critical in senescence but had no effects on ductular reactions and fibrosis. Moreover, CCR2 deletion only delayed the tumor progression that normally arises in the setting of deficient hepatocyte autophagy, but had no effects at the late stage of liver tumorigenesis.
      It is well known that autophagy-defective livers have persistent nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2 or Nrf2) activation owing to Sequestosome 1/p62-mediated noncanonical Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activation.
      • Ni H.M.
      • Woolbright B.L.
      • Williams J.
      • Copple B.
      • Cui W.
      • Luyendyk J.P.
      • Jaeschke H.
      • Ding W.X.
      Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
      Persistent Nrf2 activation is detrimental in autophagy-defective livers, which likely is owing to the impaired autophagic protein turnover and proteotoxicity.
      • Ni H.M.
      • Chao X.
      • Yang H.
      • Deng F.
      • Wang S.
      • Bai Q.
      • Qian H.
      • Cui W.
      • Shi Y.
      • Zong W.X.
      • Wang Z.
      • Yang L.
      • Ding W.X.
      Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver.
      ,
      • Yang H.
      • Ni H.M.
      • Ding W.X.
      The double-edged sword of MTOR in autophagy deficiency induced-liver injury and tumorigenesis.
      Interestingly, deletion of Nfe2l2 markedly reduced senescence in L-Atg7 KO mouse livers. Senescence often is associated with increased oxidative stress, which also occurs in autophagy-defective livers that have increased lipid peroxidation and oxidative DNA damage. It remains unclear why increased Nrf2 activation paradoxically increased oxidative stress, DNA damage, and senescence in autophagy-defective livers.
      Although this study has advanced our understanding on the mechanisms of senescence and convincingly showed hepatocyte senescence occurred in autophagy-defective mouse livers, several questions remained unanswered. The exact contribution of senescence in the pathogenesis of autophagy-defective livers remained unclear because the data only showed an indirect association of senescence with the pathogenesis of L-Atg7 KO mouse livers. Future studies to generate mice with double deficiency of autophagy and senescence by crossing L-Atg7 or L-Atg5 KO mice with either p15/Cdkn2b or p21/Cdkn1a KO mice would help to confirm the definite role of senescence in the pathogenesis of autophagy-defective livers. Senescence may have a dual role in either suppressing or promoting liver tumorigenesis in autophagy-defective livers. Notably, Huda et al
      • Huda N.
      • Khambu B.
      • Liu G.
      • Nakatsumi H.
      • Yan S.
      • Chen X.
      • Ma M.
      • Dong Z.
      • Nakayama K.I.
      • Yin X.M.
      Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.
      did not determine senescence in tumor and nontumor cells in aged L-Atg7 KO mouse livers. Therefore, future work is needed to determine whether tumor cells would escape senescence to enter a proliferating cell cycle in autophagy-defective livers.

      References

        • Aravinthan A.D.
        • Alexander G.J.M.
        Senescence in chronic liver disease: Is the future in aging?.
        J Hepatol. 2016; 65: 825-834
        • Qian H.
        • Chao X.
        • Williams J.
        • Fulte S.
        • Li T.
        • Yang L.
        • Ding W.X.
        Autophagy in liver diseases: A review.
        Mol Aspects Med. 2021; 100973
        • Ni H.M.
        • Woolbright B.L.
        • Williams J.
        • Copple B.
        • Cui W.
        • Luyendyk J.P.
        • Jaeschke H.
        • Ding W.X.
        Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
        J Hepatol. 2014; 61: 617-625
        • Khambu B.
        • Huda N.
        • Chen X.
        • Antoine D.J.
        • Li Y.
        • Dai G.
        • Köhler U.A.
        • Zong W.X.
        • Waguri S.
        • Werner S.
        • Oury T.D.
        • Dong Z.
        • Yin X.M.
        HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.
        J Clin Invest. 2018; 128: 2419-2435
        • Huda N.
        • Khambu B.
        • Liu G.
        • Nakatsumi H.
        • Yan S.
        • Chen X.
        • Ma M.
        • Dong Z.
        • Nakayama K.I.
        • Yin X.M.
        Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.
        Cell Mol Gastroenterol Hepatol. 2022; 14: 333-355
        • Ni H.M.
        • Chao X.
        • Yang H.
        • Deng F.
        • Wang S.
        • Bai Q.
        • Qian H.
        • Cui W.
        • Shi Y.
        • Zong W.X.
        • Wang Z.
        • Yang L.
        • Ding W.X.
        Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver.
        Hepatology. 2019; 70: 2142-2155
        • Acosta J.C.
        • O'Loghlen A.
        • Banito A.
        • Guijarro M.V.
        • Augert A.
        • Raguz S.
        • Fumagalli M.
        • Da Costa M.
        • Brown C.
        • Popov N.
        • Takatsu Y.
        • Melamed J.
        • d'Adda di Fagagna F.
        • Bernard D.
        • Hernando E.
        • Gil J.
        Chemokine signaling via the CXCR2 receptor reinforces senescence.
        Cell. 2008; 133: 1006-1018
        • Yang H.
        • Ni H.M.
        • Ding W.X.
        The double-edged sword of MTOR in autophagy deficiency induced-liver injury and tumorigenesis.
        Autophagy. 2019; 15: 1671-1673

      Linked Article