Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss.

Christopher Chronowski,Doug Chan,Viktor Akhanov,Ergün Sahin,Andre Catic,Milton Finegold

doi:10.3390/metabo11060394

Abstract

Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.

Highlights

Telomeres are the repetitive ends of chromosomes that are synthesized by the dedicated enzyme telomerase [1,2,3,4]
telomerase knockout mice (TKO) mice on regular chow (PicoLab, 5V5R) display normal liver architecture and contain similar triglyceride and glycogen levels compared to their wild type mice (WT) counterparts, as assessed by Oil Red O (ORO), biochemical analysis and Periodic acid– Schiff (PAS) staining (Figure 1A–D; 5–8 mice per group analyzed)
While the absence of p53 increased liver fat content in mice with and without short telomeres, our studies demonstrate that short telomeres cause profound histological and cytological abnormalities when p53 is deleted

Summary

Introduction

Telomeres are the repetitive ends of chromosomes that are synthesized by the dedicated enzyme telomerase [1,2,3,4]. Advanced telomere shortening is recognized as DNA damage by the DNA damage surveillance machinery that activates the classical p53-mediated checkpoint response of growth arrest, senescence, and apoptosis [8,9,10,11,12]. While these cellular responses are potent barriers for tumorigenesis, they are implicated in driving a variety of disorders in patients with critical short telomeres due to loss-of function mutations of telomerase (telomere biology disorders, TBD) and in the aged [13,14,15]. Accelerated telomere shortening is observed in disorders associated with high cell turnover (such as inflammatory bowel disease or hepatitis virus infection) and thought to contribute to disease progression and complications in these chronic conditions [16,17,18,19]

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Conclusion