JHEP Rep. 2021 Aug;3(4):
100301
Cellular senescence is a state of irreversible cell cycle arrest that has important physiological functions. However, cellular senescence is also a hallmark of ageing and has been associated with several pathological conditions. A wide range of factors including genotoxic stress, mitogens and inflammatory cytokines can induce senescence. Phenotypically, senescent cells are characterised by short telomeres, an enlarged nuclear area and damaged genomic and mitochondrial DNA. Secretion of proinflammatory proteins, also known as the senescence-associated secretory phenotype, is a characteristic of senescent cells that is thought to be the main contributor to their disease-inducing properties. In the past decade, the role of cellular senescence in the development of non-alcoholic fatty liver disease (NAFLD) and its progression towards non-alcoholic steatohepatitis (NASH) has garnered significant interest. Until recently, it was suggested that hepatocyte cellular senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in fatty liver disease. However, recent work in rodents has suggested that senescence may be a causal factor in NAFLD development. Although causality is yet to be established in humans, current evidence suggests that targeting senescent cells has therapeutic potential for NAFLD. We aim to provide insights into the quality of the evidence supporting a causal role of cellular senescence in the development of NAFLD in rodents and humans. We will elaborate on key cellular and molecular features of senescence and discuss the efficacy and safety of novel senolytic drugs for the treatment or prevention of NAFLD.
Keywords: ATM, ataxia telangiectasia mutated; C/EBPα, CCAAT- enhancer-binding protein; CDK, cyclin dependent kinase; DDR, DNA damage response; FFAs, free fatty acids; HCC, hepatocellular carcinoma; IL-, interleukin; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cell; MCP1/CCL2, monocyte chemoattractant protein-1; MiDAS, mitochondrial dysfunction-associated senescence; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ROS, reactive oxygen species; Rb, retinoblastoma factor; SA-β gal, senescence-associated beta-galactosidase; SASP, senescence-associated secretory phenotype; SCAP, senescence-associated antiapoptotic pathways; TGFβ, transforming growth factor-β; TNFα, tumour necrosis factor-α; cellular senescence; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; obesity; qPCR, quantitative PCR; senolytics