(HEPATOLOGY 2011;) See Editorial on Page 1430 Two models of cirrhosis formation have developed. One hypothesis indicates that cirrhosis develops as a consequence of a progressive deposition
of collagen and scar tissue PLX3397 clinical trial induced by chronic inflammation and necrosis. Another, not mutually exclusive, hypothesis indicates that telomere shortening represents an underlying cause of cirrhosis.8 Telomeres form the ends of human chromosomes. The main function of telomeres is the maintenance of chromosomal stability. However, telomeres shorten as a consequence of cell division due to the “end replication problem” of DNA polymerase, processing of telomeres during S-phase of cell cycle, and the absence of telomerase expression in most somatic tissues.9 Telomere shortening limits the proliferative life span of human cells to 50-70 cell doublings by induction
of a permanent cell Selleckchem Silmitasertib cycle arrest (replicative senescence) in response to telomere dysfunction.10, 11 Previous studies have shown that telomere shortening also limits the life span of primary human hepatocytes.12 Studies of human cirrhosis have demonstrated that telomere shortening is a general marker of cirrhosis formation correlating with an accumulation of senescent hepatocytes.13, 14 In addition, studies on telomerase-deficient mice have provided the first experimental evidence that telomere shortening limits the regenerative response to acute and chronic liver injury, accelerating the formation of liver fibrosis and steatosis.15, 16 Together, these studies have led to the telomere model of cirrhosis formation, indicating that chronic liver diseases increase the rate of cell turnover, thus leading to accelerated telomere shortening and regenerative exhaustion.8, 17 In agreement with this hypothesis, it has been recognized that proliferative activity declines after long latencies of chronic liver disease and this decline was associated with the progressive formation of disease.18
Genetic studies have proven that mutations in telomerase are the underlying cause of accelerated telomere shortening and organ failure in some rare human diseases, including some forms of dyskeratosis congenita (DKC)19 and aplastic anemia.20 4-Aminobutyrate aminotransferase In addition, 10% of the cases of familial idiopathic lung fibrosis are associated with telomerase mutations.21, 22 In most of these cases heterozygous mutations were found in either the RNA (TERC) or protein component (TERT) of telomerase. Interestingly, familial cases of idiopathic lung fibrosis and bone marrow failure also showed an increased frequency of unexplained liver pathologies, including fibrosis, inflammation, macrovesicular steatosis, and hepatic nodular regeneration.23-25 Some of these patients carried mutations in telomerase genes.