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

Author(s):Show less -

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]}

Affiliation

^[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

• Document type: Journal article
• Source: LIVER INTERNATIONAL; v. 38, n. 1, p. 144-154, JAN 2018.
• Web of Science Citations: 3

Abstract

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)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/18313-0 - Mechanisms of development of liver cirrhosis by CCl4 and schistosomiasis in Tert-/- knockout and DKC1m hypomorphic transgenic mice
• Grantee: Raquel de Melo Alves Paiva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/00449-5 - Mechanisms of development of liver cirrhosis by CCl4 and schistosomiasis in Tert-/- knockout transgenic mice
• Grantee: Raquel de Melo Alves Paiva
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor