Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis

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

doi:10.1111/liv.12049

Cited by 59 publications

(53 citation statements)

References 51 publications

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“…While rarefaction of bile ducts is a histopathologic hallmark of the disease, it is under debate whether cholangiocellular damage is the cause or consequence of the autoimmune attack towards bile ducts [2]. However, there is increasing evidence that biliary damage triggers autoimmunity in this disease [23,24]. It therefore seems crucial to better understand and characterize cholangiocellular pathophysiology in order to further unravel the pathogenesis of chronic cholangiopathies.…”

Section: Discussionmentioning

confidence: 99%

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO3- Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Wenniger

Hohenester

Maroni

et al. 2015

Dig Dis

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Background: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a ‘biliary HCO₃^- umbrella', i.e. apical cholangiocellular HCO₃^- secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the ‘biliary HCO₃^- umbrella' and thus preventing cholangiotoxicity of bile acids. Key Messages: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α_1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pK_a ≥4), but not taurochenodeoxycholate (pK_a <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. Conclusion: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the ‘biliary HCO₃^- umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.

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Section: Discussionmentioning

confidence: 99%

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO3- Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Wenniger

Hohenester

Maroni

et al. 2015

Dig Dis

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“…Since mitochondria are a major target of autophagy, we hypothesized that deregulated autophagy of mitochondria may be involved in autoimmune pathogenesis in PBC [24] . We found that the granular expression of PDC-E2 was seen in damaged small bile ducts in PBC ( fig.…”

Section: Autoimmune Process Toward Mitochondrial Antigens and Deregulmentioning

confidence: 99%

“…We found that the granular expression of PDC-E2 was seen in damaged small bile ducts in PBC ( fig. 2 ) [24] . This type of PDC-E2 expression was not seen in other control-diseased liver, such as chronic viral hepatitis [24] .…”

Section: Autoimmune Process Toward Mitochondrial Antigens and Deregulmentioning

confidence: 99%

“…2 ) [24] . This type of PDC-E2 expression was not seen in other control-diseased liver, such as chronic viral hepatitis [24] . Interestingly, the granular expression of mitochondrial antigens was co-localized with LC3 in damaged SBDs in PBC [24] .…”

Section: Autoimmune Process Toward Mitochondrial Antigens and Deregulmentioning

confidence: 99%

“…1 ) [7,8] . 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] .…”

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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Changing nomenclature for PBC: From ‘cirrhosis’ to ‘cholangitis’

et al. 2015

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Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis

Abstract: Deregulated autophagy may contribute to the abnormal expression of mitochondrial antigens and may be involved in the autoimmune pathogenesis of bile duct lesions in PBC.

Cited by 59 publications

References 51 publications

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO<sub>3</sub><sup>-</sup> Umbrella': An Integrated Line of Defense against Toxic Bile Acids

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO<sub>3</sub><sup>-</sup> Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis

Changing nomenclature for PBC: From ‘cirrhosis’ to ‘cholangitis’

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