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.

Relationship between Telomere Maintenance and Liver Disease

“…TERT inhibitors such as Tenofovir are commonly used in the long term treatment of human immunodeficiency virus (HIV) and studies have demonstrated that such use is an independent risk factor for nonalcoholic fatty liver disease (NAFLD) 22. Subsequent murine studies support a role for TERT in hepatic steatosis and hepatic injury 23…”

Telomeric zinc-finger associated protein (TZAP): a new player in telomere diseases?

“…It has been noticed that telomerase late generation knockout mice showed repression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and beta (Pgc-1α and Pgc-1β), the master regulators of mitochondrial physiology and metabolism, resulting in altered mitochondrial biogenesis and function and increased reactive oxygen (23). Consistently it has been very recently demonstrated that TERT deficient mice models, upon dietary stress, failed to engage genes involved in the metabolic response to fatty diet and presented functionally impaired mitochondria in liver cells (19). These observations represent another evidence for the involvement of liver dysfunctions in telomere diseases, and in particular a new indication that telomerase abnormalities may trigger liver disease progression from NAFLD onset to cirrhosis and cancer development.…”

“…In particular, the identification of genetic factors may be important for the risk stratification of patients in term of disease susceptibility. For instance, we recently demonstrated that short telomeres, a hallmark of cirrhosis, predispose to hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD), the most common liver disease, in which telomere attrition has been involved in disease progression (2,19). Furthermore, we found that germline mutations in telomerase reverse transcriptase (TERT) are enriched in NAFLD-HCC patients (20,21).…”

Hepatic Senescence Accompanies the Development of NAFLD in Non-Aged Mice Independently of Obesity

“…In humans, several studies implicate telomere shortening in NAFLD and indicate it as a potential marker or therapeutic target, although its role as a disease cause has not yet been proven [ 31 ]. A study in mice suggests that telomeropathies and short telomeres can cause metabolic dysfunction in hepatocytes [ 32 ]. The absence of considerable change in telomere length in our models indicates that telomere shortening is not involved in NAFLD development in the models used herein, implying that the emergence of NAFLD in non-aged organisms does not correlate with changes in telomere length.…”