Telomere Dysfunction in Nonalcoholic Fatty Liver Disease and Cryptogenic Cirrhosis

Abstract

Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism.

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

“…(49) Similarly, Laish et al showed that patients with NAFLD had shorter telomeres in their peripheral lymphocytes and higher expression of telomerase reverse transcriptase mRNA as compared with healthy controls. (50) These findings support the role of telomere dysfunction and senescence in general in NAFLD.…”

“…Patients who developed NAFLD within this period had shorter telomeres in peripheral blood leukocytes at the end of the follow‐up period compared with the patients who did not develop steatosis . Similarly, Laish et al showed that patients with NAFLD had shorter telomeres in their peripheral lymphocytes and higher expression of telomerase reverse transcriptase mRNA as compared with healthy controls . These findings support the role of telomere dysfunction and senescence in general in NAFLD.…”

Leucocyte telomere shortening is associated with nonalcoholic fatty liver disease‐related advanced fibrosis

“…Indeed, a recent study showed that hepatocyte senescence, not hepatocyte telomere shortening, is closely associated with fibrosis stage, disease progression and adverse liver‐related outcomes . Other studies have also found that shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD compared to the healthy controls along with genetic and environmental risk factors . Additionally, there is evidence that elevated inflammation, as observed in NASH with fibrosis, may be a consequence of premature immunosenescence .…”

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

“…In addition to chronic lung diseases, telomere shortening has been evinced to drive the progression of liver cirrhosis in both hepatocytes and senescence associated with fibrotic scaring 8 . Apart from telomeres in the liver-specific cells, several clinical studies uncovered telomere attrition in blood leukocytes of patients with chronic liver diseases [10][11][12][13][14][15] . Collectively, it seems plausible that aberrant telomere length could be an important mediator for hepatocyte damage and turnover, and alterations in telomere length would open a unique opportunity for early detection of ATDILI progression in tuberculosis patients.…”