Insulin-like growth factor-1 attenuates oxidative stress-induced hepatocyte premature senescence in liver fibrogenesis via regulating nuclear p53–progerin interaction

作者：Xiaoying Luo, Xiaoke Jiang, Jun Li, Yangqiu Bai, Zhen Li, Pei‐Ru Wei, Suofeng Sun, Yuan Liang, Shuangyin Han, Xiuling Li, Bingyong Zhang · 发表于：Cell Death and Disease · 年份：2019 · DOI：10.1038/s41419-019-1670-6 · 被引用次数：61 · 研究领域：Nuclear Structure and Function、Cancer-related Molecular Pathways、Liver physiology and pathology

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 CCl 4 -induced liver injury rat models. Nevertheless, IGF-1 gene transfer to CCl 4 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, H 2 O 2 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 H 2 O 2 -treated hepatocytes, reversed oxidative stress-...