{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:14:21Z","timestamp":1787170461256,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,8,19]],"date-time":"2017-08-19T00:00:00Z","timestamp":1503100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["13\/08135\u20102"],"award-info":[{"award-number":["13\/08135\u20102"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["11\/18313\u20100"],"award-info":[{"award-number":["11\/18313\u20100"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["12\/00449\u20105"],"award-info":[{"award-number":["12\/00449\u20105"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background &amp; Aims<\/jats:title>\n                    <jats:p>\n                      Short telomeres and genetic telomerase defects are risk factors for some human liver diseases, ranging from non\u2010alcoholic fatty liver disease and non\u2010alcoholic steatohepatitis to cirrhosis. In murine models, telomere dysfunction has been shown to metabolically compromise hematopoietic cells, liver and heart via the activation of the p53\u2010\n                      <jats:styled-content style=\"fixed-case\">PGC<\/jats:styled-content>\n                      axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Tert<\/jats:italic>\n                      \u2010 and\n                      <jats:italic>Terc<\/jats:italic>\n                      \u2010deficient mice were challenged with liquid high\u2010fat diet. Liver metabolic contents were analysed by\n                      <jats:styled-content style=\"fixed-case\">CE<\/jats:styled-content>\n                      \u2010\n                      <jats:styled-content style=\"fixed-case\">TOFMS<\/jats:styled-content>\n                      and liver fat content was confirmed by confocal and electronic microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Tert<\/jats:italic>\n                      \u2010deficient but not\n                      <jats:italic>Terc<\/jats:italic>\n                      \u2010deficient mice develop hepatocyte injury and frank steatosis when challenged with liquid high\u2010fat diet. Upon high\u2010fat diet,\n                      <jats:italic>Tert<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      hepatocytes fail to engage the citric acid cycle (\n                      <jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content>\n                      ), with an imbalance of\n                      <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content>\n                      \/\n                      <jats:styled-content style=\"fixed-case\">NADP<\/jats:styled-content>\n                      <jats:sup>+<\/jats:sup>\n                      and\n                      <jats:styled-content style=\"fixed-case\">NADH<\/jats:styled-content>\n                      \/\n                      <jats:styled-content style=\"fixed-case\">NAD<\/jats:styled-content>\n                      <jats:sup>+<\/jats:sup>\n                      ratios and depletion of intermediates of\n                      <jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content>\n                      cycle, such as cis\u2010aconitic acid. Telomerase deficiency caused an intrinsic metabolic defect unresponsive to environmental challenge. Chemical inhibition of telomerase by zidovudine recapitulated the abnormal\n                      <jats:italic>Tert<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      metabolic phenotype in\n                      <jats:italic>Terc<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      hepatocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicate that in telomeropathies short telomeres are not the only molecular trigger and telomerase enzyme deficiency provokes hepatocyte metabolic dysfunction, abrogates response to environmental challenge, and causes cellular injury and steatosis, providing a mechanism for liver damage in telomere diseases.<\/jats:p>\n                  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