A possible involvement of p62/sequestosome‐1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis

Sasaki, Motoko; Miyakoshi, Masami; Sato, Yasunori; Nakanuma, Yasuni

doi:10.1111/j.1478-3231.2011.02656.x

Cited by 52 publications

(48 citation statements)

References 54 publications

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“…Thus, autophagy inhibition accelerates the development of senescence and apoptosis, although this theory is controversial [10]. The co-regulation of p62 and LC3 causes dual effects on autophagic and senescent responses: decreases in autophagic and senescent programs or increases in autophagic and senescent biomarkers have been reported [35]. This paradox also appears in the inhibition of atg5, atg7 and atg3, which are accompanied by no change in apoptosis [36,37,38].…”

Section: Discussionmentioning

confidence: 99%

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Chen

Bin

Xiao

et al. 2014

Cell Physiol Biochem

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Backgrounds: Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear. Methods and Results: We studied high-glucose-induced renin-angiotensin system (RAS)-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang). The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL)-positive cells, β-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses. Conclusions: These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Chen

Bin

Xiao

et al. 2014

Cell Physiol Biochem

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“…Deregulated autophagy in cholangiocytes may be involved in the pathogenesis of PBC [7,8] . We disclosed the accumulation of autophagy marker LC3-positive vesicles in the damaged small bile ducts in the bile duct lesion (CNSDC) in PBC ( fig.…”

Section: Cholangiocyte Autophagy/deregulated Autophagy In Pbcmentioning

confidence: 99%

“…Furthermore, the aggregation of p62 is specifically increased together with the accumulation of LC3-positive vesicles in damage bile ducts in PBC ( fig. 2 ) [8] . The accumulation of autophagic vacuoles was ultrastructurally confirmed in cholangiocytes in damaged bile ducts in PBC [8] .…”

Section: Cholangiocyte Autophagy/deregulated Autophagy In Pbcmentioning

confidence: 99%

“…Deregulated autophagy may be related to the autoimmune process against mitochondrial antigens in PBC [9] . Furthermore, deregulated autophagy may precede cellular senescence in bile duct lesions in PBC [7,8] . Although exact mechanisms of deregulated autophagy remain unclear, an involvement of endoplasmic reticulum (ER) stress induced by GCDC in cholangiocytes is suggested [10] .…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidences suggest that deregulated autophagy may be a central player in the pathogenesis of PBC ( fig. 1 ) [7,8] . Deregulated autophagy may be related to the autoimmune process against mitochondrial antigens in PBC [9] .…”

Section: Introductionmentioning

confidence: 99%

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Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis

Sasaki

Nakanuma²

2017

Dig Dis

Self Cite

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Background: Primary biliary cholangitis (PBC) is characterized by a high prevalence of serum anti-mitochondrial antibodies against the E2 subunit of the pyruvate dehydrogenase complex and bile duct lesions called chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. Macroautophagy (a major type of autophagy) is a process of cellular self-digestion that plays a critical role in energy homeostasis and in the cytoprotection to various stresses. Deregulated autophagy is thought to be associated with various human diseases. Key Messages: Accumulating evidences suggest that deregulated autophagy may be a central player in the pathogenesis of PBC. Damaged cholangiocytes involved in CNSDC show vesicular expression of autophagy marker LC3 and accumulation of p62/sequestosome-1, suggesting deregulated autophagy. Deregulated autophagy may be involved in the autoimmune process via the abnormal expression of mitochondrial antigens and also in cholangiocyte senescence in bile duct lesions in PBC. In vitro study showed that hydrophobic bile acids, such as glycochenodeoxycholic acid (GCDC), as well as serum deprivation and oxidative stress, cause autophagy, deregulated autophagy and abnormal expression of mitochondrial antigens followed by cellular senescence in cholangiocytes. Although exact mechanisms of deregulated autophagy remain to be clarified, endoplasmic reticulum (ER) stress may be a plausible cause of deregulated autophagy induced by GCDC in cholangiocytes. Impaired ‘biliary bicarbonate umbrella' may further exacerbate the toxicity of GCDC to cholangiocytes. Interestingly, pretreatment with ursodeoxycholic acid (UDCA) and tauro-UDCA, which is a chemical chaperone enhancing the adaptive capacity of the ER, significantly suppressed ER stress, deregulated autophagy and cellular senescence induced by GCDC and other stresses in cholangiocytes. Conclusions: GCDC may play a role in the occurrence of deregulated autophagy and cellular senescence at least partly through the induction of ER stress in PBC. Deregulated autophagy and cellular senescence can be a promising therapeutic target in PBC.

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Mesenchymal stem cells enhance autophagy of human intrahepatic biliary epithelial cells in vitro

Zhu

Wang

Tang

et al. 2018

Cell Biochemistry & Function

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The present findings constitute the first report that human umbilical cord-derived MSCs enhance autophagic flux in HiBECs through a STAT3-dependent way: MSCs enhance the autophagic flux by increasing the formation of autophagosome and autolysosome in GCDC-treated HiBECs. MSCs decrease the STAT3 activity and the expression of eIF2α in GCDC-treated HiBECs; in addition, MSCs increase the expression of PKR. With STAT3 silencing, MSCs enhance neither the levels of LC3II nor the expression of PKR in GCDC-treated HiBECs.

show abstract

A possible involvement of p62/sequestosome‐1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis

Abstract: The aggregation of p62 is specifically increased in the damage bile ducts in PBC and may reflect dysfunctional autophagy, followed by cellular senescence in the pathogenesis of bile duct lesions in PBC.

Cited by 52 publications

References 54 publications

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis

Mesenchymal stem cells enhance autophagy of human intrahepatic biliary epithelial cells in vitro

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