Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis
Open accessAbstract
Recent studies disclosed that autophagy is induced during and facilitates the process of senescence. Given that biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features, we examined an involvement of autophagy in the process of biliary epithelial senescence in PBC. We examined immunohistochemically the expression of microtubule-associated proteins-light chain 3beta (LC3), a marker of autophagy, in livers taken from the patients with PBC (n=37) and control livers (n=75). We also examined the co-localization of LC3 with autophagy-related cathepsin D, lysosome-associated membrane protein-1 (LAMP-1), and senescent markers, p16(INK4a) and p21(WAF1/Cip1). We examined the effect of autophagy inhibitor (3-methyladenine) on the induction of cellular senescence and senescence-associated secretion (CCL2 and CX3CL1) in cultured murine BECs. The expression of LC3 was specifically seen in vesicles in BECs in the inflamed and damaged small bile ducts in PBC, when compared with non-inflamed small bile ducts in PBC and in control livers (P<0.01). The expression of LC3 was closely related to the expression of cathepsin D, LAMP-1, and senescent markers. In cultured BECs, oxidative stress, DNA damage, and serum deprivation induced cellular senescence, when compared with control and the inhibition of autophagy significantly decreased the stress-induced cellular senescence (P<0.01). Furthermore, the secretion level of CCL2 and CX3CL1 increased significantly by various stress and suppressed by the inhibition of autophagy (P<0.01). In conclusion, autophagy is specifically seen in the damaged small bile ducts along with cellular senescence in PBC. The inhibition of autophagy suppressed cellular senescence in cultured cells. These findings suggest that autophagy may mediate the process of biliary epithelial senescence and involve in the pathogenesis of bile duct lesions in PBC.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increasing data indicate a significant association between senescence and autophagy in various cell systems.
“Increasing data indicate a significant association between senescence and autophagy in various cell systems (Gerland et al. 2003; Gamerdinger et al. 2009; Sasaki et al. 2010; Capparelli et al. 2012; Dörr et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Sasaki et al. 2010
Cites
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · see citing works
Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · cited 1× · see citing works
“8 and the senescence-associated secretory phenotypes (SASP)”
BackgroundMolecular dissection of autophagy: two ubiquitin-like systems
Ohsumi, Y. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35056522 · Cited by 1,240 · see citing works
Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M., & Green, M. R. (2008) · Cell · doi:10.1016/j.cell.2007.12.032 · Cited by 903 · see citing works
A novel role for high-mobility group A proteins in cellular senescence and heterochromatin formation
Narita, M., Narita, M., Krizhanovsky, V., Nuñez, S., Chicas, A., Hearn, S. A., Myers, M. P., & Lowe, S. W. (2006) · Cell · doi:10.1016/j.cell.2006.05.052 · Cited by 629 · see citing works
Kita, H., Matsumura, S., He, X.-S., Ansari, A. A., Lian, Z.-X., Van de Water, J., Coppel, R. L., Kaplan, M. M., & Gershwin, M. E. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214698 · Cited by 222 · see citing works
Nakanuma, Y., & Ohta, G. (1979) · Gastroenterology · doi:10.1016/0016-5085(79)90396-2 · Cited by 213 · see citing works
Self-citationSmall-duct primary sclerosing cholangitis
Ludwig, J. (1991) · Seminars in Liver Disease · doi:10.1055/s-2008-1040417 · Cited by 166 · see citing works
Sasaki, M., Ikeda, H., Yamaguchi, J., Nakada, S., & Nakanuma, Y. (2008) · Hepatology · doi:10.1002/hep.22348 · Cited by 125 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
A role for autophagy during hepatic stellate cell activation
Thoen, L. F. R., Guimarães, E. L. M., Dollé, L., Mannaerts, I., Najimi, M., Sokal, E., & van Grunsven, L. A. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.07.010 · Cited by 385 · see citing works
Various modes of cell death induced by DNA damage
Surova, O., & Zhivotovsky, B. (2013) · Oncogene · doi:10.1038/onc.2012.556 · Cited by 334 · see citing works
Capparelli, C., Chiavarina, B., Whitaker-Menezes, D., Pestell, T. G., Pestell, R. G., Hulit, J., Andò, S., Howell, A., Martinez-Outschoorn, U. E., Sotgia, F., et al. (2012) · Cell Cycle · doi:10.4161/cc.21884 · Cited by 221 · see citing works
Autophagy and senescence: A partnership in search of definition
Gewirtz, D. A. (2013) · Autophagy · doi:10.4161/auto.23922 · Cited by 166 · see citing works
Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments
Baisantry, A., Bhayana, S., Rong, S., Ermeling, E., Wrede, C., Hegermann, J., Pennekamp, P., Sörensen-Zender, I., Haller, H., Melk, A., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111059 · Cited by 97 · see citing works
Cell senescence as both a dynamic and a static phenotype
Young, A. R. J., Narita, M., & Narita, M. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_1 · Cited by 50 · see citing works
The immunological landscape of primary biliary cholangitis: Mechanisms and therapeutic prospects
Ronca, V., Davies, S. P., Oo, Y. H., & Lleo, A. (2025) · Hepatology · doi:10.1097/hep.0000000000001225 · Cited by 22 · see citing works
- Authors
- Sasaki, M., Miyakoshi, M., Sato, Y., & Nakanuma, Y.
- Affiliations
- Kanazawa University (JP)
- Corresponding author
- Nakanuma, Yasuni
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 90
- Issue
- 6
- Pages
- 835-843
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2044722165
- Cited by
- 114
- References
- 9
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 7 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 12 · 2016: 9 · 2015: 8 · 2014: 16 · 2013: 7 · 2012: 10
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-06-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- autophagy, cellular senescence, primary biliary cirrhosis, cholangiocytes, bile duct injury, LC3, cathepsin D, LAMP1, p16INK4a, p21, 3-methyladenine, MCP-1, fractalkine, oxidative stress, DNA damage, serum deprivation, liver inflammation
- MeSH terms
- Autophagy, Bile Ducts, Bile Ducts, Intrahepatic, Enzyme-Linked Immunosorbent Assay, Gallbladder, Humans, Liver, Liver Cirrhosis, Biliary, Immunoblotting, Interleukin-8, Cellular Senescence, Bile Ducts, Extrahepatic, Chemokine CCL2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
