TY - JOUR
T1 - Evaluating causality of cellular senescence in non-alcoholic fatty liver disease
AU - Meijnikman, Abraham Stijn
AU - Herrema, Hilde
AU - Scheithauer, Torsten Pascal Marcel
AU - Kroon, Jeffrey
AU - Nieuwdorp, Max
AU - Groen, Albert Kornelis
N1 - Funding Information: M. Nieuwdorp is supported by a ZONMW-VIDI , Netherlands grant 2013 [016.146.327] and a grant from the Dutch Heart Foundation , Netherlands, CVON IN CONTROL. HH is supported by a Senior Fellowship (2019.82.004) of the Dutch Diabetes Research Foundation . JK received a VENI grant by ZONMW ( 91619098 ). Funding Information: M. Nieuwdorp is supported by a ZONMW-VIDI, Netherlands grant 2013 [016.146.327] and a grant from the Dutch Heart Foundation, Netherlands, CVON IN CONTROL. HH is supported by a Senior Fellowship (2019.82.004) of the Dutch Diabetes Research Foundation. JK received a VENI grant by ZONMW (91619098). Publisher Copyright: © 2021 The Author(s)
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - cellular senescence
KW - non-alcoholic fatty liver disease
KW - non-alcoholic steatohepatitis
KW - obesity
KW - senolytics
UR - http://www.scopus.com/inward/record.url?scp=85106517048&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jhepr.2021.100301
DO - https://doi.org/10.1016/j.jhepr.2021.100301
M3 - Review article
C2 - 34113839
SN - 2589-5559
VL - 3
JO - JHEP Reports
JF - JHEP Reports
IS - 4
M1 - 100301
ER -