Abstract
Stress-induced premature senescence (SIPS), a state of cell growth arrest due to various stimuli, is implicated in the pathogeneses of hepatic fibrogenesis. Progerin, a permanently farnesylated mutant lamin A protein, likely leads to premature senescence to influent liver diseases. The previous reports showed that activation of insulin-like growth factor-1 (IGF-1) signaling could enhance cell longevity and attenuate liver fibrosis. However, the underlying mechanisms about hepatocyte premature senility in liver fibrosis, and how IGF-1 regulates cell premature aging and fibrogenesis, remain poorly understood. In the present study, we found the augment of hepatocyte oxidation and premature aging, along with the decrease of plasm IGF-1 level in patients with liver fibrosis and CCl4-induced liver injury rat models. Nevertheless, IGF-1 gene transfer to CCl4 rats to overexpress intrahepatic IGF-1 relieved hepatocyte oxidative stress and premature senescence, which was likely mediated by the p53/progerin pathway, to improve hepatic steatosis and fibrogenesis. In vitro, H2O2 caused abnormal accumulation of progerin in nuclear and activation of nuclear p53–progerin interaction to trigger primary rat hepatocyte premature senescence through the p21-independent pathway; while these effects were rescued by prolonged exogenous IGF-1 or the IGF-1 adenovirus vector. Furthermore, the IGF-1 adenovirus vector, transfected to H2O2-treated hepatocytes, reversed oxidative stress-induced premature senescence via enhancing cytoplasmic AKT1–p53 interaction and subsequently inhibiting nuclear p53–progerin interaction. Consequently, our data illuminate a novel role of IGF-1 in regulating stress-induced hepatocyte premature senescence in liver fibrosis: prolonged IGF-1 relieves oxidative stress-initiated hepatocyte premature senescence via inhibition of nuclear p53–progerin interaction to ameliorate hepatic steatosis and fibrogenesis.
Highlights
Stress-induced premature senescence (SIPS), a kind of replicative senescence due to depletion of cell proliferative potential, is caused by a variety of sublethal stresses, such as H2O2, hypoxia, or hyperoxia[1]
Our present study aims to investigate the role of insulin-like growth factor-1 (IGF-1) in hepatocyte premature senescence in liver fibrosis mediated by progerin
These suggested that the increased expression of nuclear p53 and progerin in intrahepatic cells could be strongly linked to cell premature senescence in human liver fibrosis
Summary
Stress-induced premature senescence (SIPS), a kind of replicative senescence due to depletion of cell proliferative potential, is caused by a variety of sublethal stresses, such as H2O2, hypoxia, or hyperoxia[1]. Excessive stress-induced premature aging triggers abnormal accumulation of senescent like-cells to affect cell function, tissue repair, as well as aging-related disorders and diseases. Luo et al Cell Death and Disease (2019)10:451 studies have provided critical insights on the close relation between premature senescence and liver diseases. During aging, oxidative stress-induced mitochondrial DNA mutations triggered a vicious cycle with increasing production of reactive oxygen species (ROS) to accelerate liver ballooning degeneration[4]. These results imply that oxidative stress causes cell premature aging to aggravate liver injury. Elucidation of the underlying mechanisms for cell premature senility may be a key to our understanding of liver fibrosis pathogenesis
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