Telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes upon dietary stress

Autor(es):Mostrar menos -

Alves-Paiva, Raquel M. ^{[1, 2, 3]} ; Kajigaya, Sachiko ^[3] ; Feng, Xingmin ^[3] ; Chen, Jichun ^[3] ; Desierto, Marie ^[3] ; Wong, Susan ^[3] ; Townsley, Danielle M. ^[3] ; Donaires, Flavia S. ^[1] ; Bertola, Adeline ^[4] ; Gao, Bin ^[4] ; Young, Neal S. ^[3] ; Calado, Rodrigo T. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Sao Paulo Res Fdn FAPESP, Ctr Cell Based Therapy, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Internal Med, Ribeirao Preto, SP - Brazil

^[3] NIAAA, Hematol Branch, NHLBI, NIH, Bethesda, MD - USA

^[4] NIAAA, Lab Liver Dis, NIH, Bethesda, MD - USA

• Tipo de documento: Artigo Científico
• Fonte: LIVER INTERNATIONAL; v. 38, n. 1, p. 144-154, JAN 2018.
• Citações Web of Science: 3

Resumo

Background \& AimsShort telomeres and genetic telomerase defects are risk factors for some human liver diseases, ranging from non-alcoholic fatty liver disease and non-alcoholic 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-PGC axis. MethodsTert- and Terc-deficient mice were challenged with liquid high-fat diet. Liver metabolic contents were analysed by CE-TOFMS and liver fat content was confirmed by confocal and electronic microscopy. ResultsTert-deficient but not Terc-deficient mice develop hepatocyte injury and frank steatosis when challenged with liquid high-fat diet. Upon high-fat diet, Tert(-/-) hepatocytes fail to engage the citric acid cycle (TCA), with an imbalance of NADPH/NADP(+) and NADH/NAD(+) ratios and depletion of intermediates of TCA cycle, such as cis-aconitic acid. Telomerase deficiency caused an intrinsic metabolic defect unresponsive to environmental challenge. Chemical inhibition of telomerase by zidovudine recapitulated the abnormal Tert(-/-) metabolic phenotype in Terc(-/-) hepatocytes. ConclusionsOur 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. See Editorial on Page 33 (AU)

• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 11/18313-0 - Mecanismos de desenvolvimento de cirrose hepática induzida por CCl4 e Schistossoma mansoni em camundongos "knockout" do gene da telomerase (Tert-/-) e Dkc1 hipomórfico (Dkc1m)
• Beneficiário: Raquel de Melo Alves Paiva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/00449-5 - Mecanismos de desenvolvimento de cirrose hepática induzida por CCl4 e Schistossoma mansoni em camundongos knockout do gene da telomerase (Tert-/-)
• Beneficiário: Raquel de Melo Alves Paiva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado