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

Abstract

BACKGROUND & AIMS:

Short 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.

METHODS:

Tert- 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.

RESULTS:

Tert-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.

CONCLUSIONS:

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.

• Authors: Raquel M Alves-Paiva, Sachiko Kajigaya, Xingmin Feng, Jichun Chen, Marie Desierto, Susan Wong, Danielle M Townsley, Flávia S Donaires, Adeline Bertola, Bin Gao, Neal S Young, Rodrigo T Calado
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 38 Issue 1 Pg. 144-154 (01 2018) ISSN: 1478-3231 [Electronic] United States
• PMID: 28741793 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• telomerase RNA
• Zidovudine
• RNA
• Telomerase
• Tert protein, mouse

Topics

• Animals
• Blood Glucose (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Enzyme Inhibitors (pharmacology)
• Fatty Liver (blood, enzymology, genetics, pathology)
• Hepatocytes (drug effects, enzymology, pathology)
• Lipid Metabolism (drug effects, genetics)
• Liver (drug effects, enzymology, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• RNA (genetics)
• Telomerase (antagonists & inhibitors, deficiency, genetics)
• Telomere Shortening
• Zidovudine (pharmacology)