Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

Meadows, Vik; Baiocchi, Leonardo; Kundu, Debjyoti; Sato, Keisaku; Fuentes, Yessenia; Wu, Chaodong; Chakraborty, Sanjukta; Glaser, Shannon; Alpini, Gianfranco; Kennedy, Lindsey; Francis, Heather

doi:10.3389/fmolb.2021.803098

Cited by 18 publications

(18 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, we investigated the expression of senescence and SASP-related genes in a published RNA sequencing dataset from Andersson et al , obtained from pediatric ALGS (n = 5) and cholestatic (n = 2)/non-cholestatic (n = 2) control livers (GSE104873) [ 11 ]. We only considered the results of the differential expression analysis comparing ALGS to non-cholestatic controls since oxidative stress due to bile acids accumulation can per se lead to premature senescence in cholestatic diseases [ 12 ]. Also, ALGS and cholestatic livers clustered together in the principal component analysis of the study and were distinct from the transcriptomes of the two non-cholestatic controls suffering from autoimmune hepatitis [ 11 ].…”

Section: Resultsmentioning

confidence: 99%

Premature senescence of the liver in Alagille patients

et al. 2023

View full text Add to dashboard Cite

Introduction Alagille syndrome (ALGS) is an autosomal dominant disease characterized by a multisystem involvement including bile duct paucity and cholestasis, caused by JAG1 or NOTCH2 mutations in most of the cases. Jagged1-Notch2 interactions are known to be crucial for intrahepatic biliary tract development, but the Notch signaling pathway is also involved in the juxtacrine transmission of senescence and in the induction and modulation of the senescence-associated secretory phenotype (SASP). Aim Our aim was to investigate premature senescence and SASP in ALGS livers. Methods Liver tissue from ALGS patients was prospectively obtained at the time of liver transplantation (n = 5) and compared to control livers (n = 5). Results We evidenced advanced premature senescence in the livers of five JAG1 mutated ALGS pediatric patients through increased senescence-associated beta-galactosidase activity (p<0.05), increased p16 and p21 gene expression (p<0.01), and increased p16 and γH2AX protein expression (p<0.01). Senescence was located in hepatocytes of the whole liver parenchyma as well as in remaining bile ducts. The classical SASP markers TGF-β1, IL-6, and IL-8 were not overexpressed in the livers of our patients. Conclusions We demonstrate for the first time that ALGS livers display important premature senescence despite Jagged1 mutation, underlying the complexity of senescence and SASP development pathways.

show abstract

Section: Resultsmentioning

confidence: 99%

Premature senescence of the liver in Alagille patients

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Senescent cholangiocytes may also contribute to liver fibrosis ( 74 ). However, these cells are primarily involved in cholestatic disorders, and their role in the development of NAFLD is only suggested by studies in mouse models ( 75 ). Thus, senescent cholangiocytes are not covered in depth here.…”

Section: Increased Senescence In Key Metabolic Human Tissuesmentioning

confidence: 99%

Increased cell senescence in human metabolic disorders

Spinelli¹,

Baboota²,

Gogg³

et al. 2023

Journal of Clinical Investigation

View full text Add to dashboard Cite

Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.

show abstract

“…2 ). Cellular senescence is a pathophysiological state in which proliferating cells enter cell cycle arrest following DNA damage and other stresses [ 53 ]. BAs have been identified as potent inducers of cellular senescence [ 54 , 55 ].…”

Section: Bas In Cholestatic Liver Diseasesmentioning

confidence: 99%

“…Cholangiocyte senescence is considered a key pathogenic process in cholestatic disease progression [ 56 , 62 , 63 ]. One potential mechanism is the persistent secretion of fibro-inflammatory mediators through SASP [ 53 ]. The work of Barron-Millar et al highlights the importance of cholangiocyte senescence in the pathogenesis of PBC.…”

Section: Bas In Cholestatic Liver Diseasesmentioning

confidence: 99%

Bile acid-mediated signaling in cholestatic liver diseases

Zeng¹,

Fan²,

Zhou³

2023

Cell Biosci

View full text Add to dashboard Cite

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

show abstract

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

Cited by 18 publications

References 131 publications

Premature senescence of the liver in Alagille patients

Premature senescence of the liver in Alagille patients

Increased cell senescence in human metabolic disorders

Bile acid-mediated signaling in cholestatic liver diseases

Contact Info

Product

Resources

About