Premature telomere shortening and impaired regenerative response in hepatocytes of individuals with NAFLD.
OBJECTIVE
The risk factors associated with poor prognosis of nonalcoholic fatty liver disease (NAFLD) are not fully understood. Our aim was to assess the role of progressive hepatocellular telomere shortening in the clinical course of NAFLD.


METHODS
We measured average telomere lengths in liver tissue samples from 44 patients with NAFLD by quantitative fluorescence in situ hybridization using a telomere-specific probe. Patients in which telomeres measured at least 80% of the lengths of age-matched controls were categorized as group A. Those patients with telomeres measuring less than 80% of the control lengths formed group B.


RESULTS
Within group B, some samples showed a remarkable shortening of hepatocyte telomeres in younger patients, whereas some group A patients showed almost normal telomere lengths until their seventies. Among clinicopathological factors, body mass index (BMI), homeostasis model assessment insulin resistance (HOMA-IR), histological degree of steatosis and intensity of 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunostaining were all significantly higher in group B than in group A. Ki-67 immunohistochemistry demonstrated that group B liver tissues were significantly less proliferative than those from group A, despite no significant difference in the necroinflammatory activities of group A and B samples. In group B patients, the ratios of Ki-67 positive index to alanine aminotransferase value were significantly lower than group A.


CONCLUSIONS
Greater insulin resistance can result in more severe hepatic steatosis among group B patients, leading to an overproduction of reactive oxygen species, which may accelerate telomere erosion. Furthermore the regenerative response of hepatocytes with prominent telomere shortening may be impaired, making these cells vulnerable to the effect of a 'second-hit' insult.
Nakajima
Tomoki
T
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan. tomnaka@silver.ocn.ne.jp
Moriguchi
Michihisa
M
Katagishi
Tatsuo
T
Sekoguchi
Satoru
S
Nishikawa
Taichirou
T
Takashima
Hidetaka
H
Kimura
Hiroyuki
H
Minami
Masahito
M
Itoh
Yoshito
Y
Kagawa
Keizo
K
Tani
Yoichi
Y
Okanoue
Takeshi
T
D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002478:Cells, Cultured; D043171:Chromosomal Instability; D018450:Disease Progression; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007333:Insulin Resistance; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D011336:Probability; D011379:Prognosis; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D016615:Telomere / Q000235:genetics*