The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis

Zhou, Xiaodong; Xie, Li; Bergmann, Frank; Endris, Volker; Strobel, Oliver; Büchler, Markus W.; Kroemer, Guido; Hackert, Thilo; Fortunato, Franco

doi:10.1038/cddiscovery.2017.27

Cited by 25 publications

(23 citation statements)

References 46 publications

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“…Accumulation of bile acid suppresses autophagy in pancreatic acinar cells signals via elevating the expression of nuclear farnesoid X receptor (FXR). FXR diminishes the expression of ATG7 and thereby triggeres inflammation and fibrosis in CP 17 . Besides, tocotrienol-rich fraction activates autophagic death in activated PSCs.…”

Section: Introductionmentioning

confidence: 99%

RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis

Wang

et al. 2018

Cell Death Dis

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Chronic pancreatitis (CP) is described as a progressive fibro-inflammatory disorder of the exocrine disease, which eventually leads to damage of the gland. Excessive activation of pancreatic stellate cells (PSCs) is a critical participant in the initiation of CP. Autophagy is involved in multiple degeneration and inflammation in acute pancreatitis and CP. In our study, we report that retinoblastoma coiled coil protein 1 (RB1CC1) expression and the autophagic level are elevated in activated PSCs. RB1CC1 is positively correlated with pancreatic fibrogenesis in tissues and plasma of CP patients. Knockdown of RB1CC1 restrains alpha smooth muscle actin (α-SMA) and collagen expressions, and autophagy in activated PSCs in vitro. Furthermore, we show that RB1CC1 induces PSC activation via binding to ULK1 promoter and the direct interaction with ULK1 protein. These suppress ULK1 expression and its kinase activity. In mice, knockdown of RB1CC1 blocks autophagy and then inhibits the pancreatic duct ligation-induced pancreatic fibrosis. Consequently, our study highlights that RB1CC1-mediated autophagy is a key event for the activation of PSCs. Inhibition of RB1CC1 alleviates autophagy, which plays a critical role in anti-fibrotic activation in PSCs and CP progression. RB1CC1 could be a novel strategy for the treatment of pancreatic fibrosis.

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Section: Introductionmentioning

confidence: 99%

RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis

Wang

et al. 2018

Cell Death Dis

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“…This mechanism was confirmed in TGR5 ligand ameliorating the immunity of intestinal mucosa in experimental colitis [41]. Moreover, in the pancreas, local accumulation of BAs molecules could inhibit autophagy of pancreatic acinar cells through FXR, leading to the increasing of apoptosis and necrotic apoptosis [42]. Our team previously found that the administration of INT-777 could protect AP in mice and improve pancreatic acinar cell necrosis [43].…”

Section: Discussionmentioning

confidence: 67%

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Xie

et al. 2020

Preprint

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Background Recent studies have shown that bile acids (BAs) are closely related to metabolic and inflammatory diseases. Our study aimed to investigate whether circulating total bile acid (TBA) levels were associated with the severity of acute pancreatitis (AP). Methods We retrospectively collected data on patients diagnosed with AP in a tertiary center from 01 January 2014 to 31 December 2016. The highest TBA value during the first 1,2,3,5,7 days after admission was determined as D1, D2, D3, D5, D7 TBA max . Patients were divided into the high TBA (HTBA) group and the normal TBA (NTBA) group according to whether the TBA max was ≥10μmol/L. The prognosis and complications, including death, organ failure (OF) and pancreatic necrosis, were compared between the two groups. Logistic regression analysis and receiving operating characteristic (ROC) curve were used to evaluate the relationship between circulating TBA and organ failure in AP patients. Results Through stratified analysis of each time period, we found that the incidence of OF in the HTBA group was significantly higher than that in the NTBA group, and the AP severity classification in the HTBA group was more serious than that in the NTBA group. In addition, according to the D7 TBA max values, the pancreatic necrosis rate, percutaneous catheter drainage (PCD) rate and mortality in the HTBA group were higher than those in the NTBA group. Multivariate regression analysis showed that HTBA (odds ratio (OR), 4.894; P = 0.002) was an independent risk factor for AP complicated with OF, which was verified in the grouping based on D7 TBA max . ROC analysis revealed that a circulating D7 TBA max cutoff point of 6.450 umol/L had optimal predictive value for the development of OF in AP patients with an area under the curve of the ROC curve (AUCROC) of 0.777. Conclusions The increase of circulating TBA in early stage of AP is independently related to organ failure, which indicates the adverse prognosis of AP patients.

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Section: Discussionmentioning

confidence: 72%

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Xie

Dong

et al. 2020

BMC Gastroenterol

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Background: Recent studies have shown that bile acids (BAs) are closely related to metabolic and inflammatory diseases. Our study aimed to investigate whether circulating total bile acid (TBA) levels were associated with the severity of acute pancreatitis (AP). Methods: We retrospectively collected data on patients diagnosed with AP in a tertiary center from 01 January 2014 to 31 December 2016. The highest TBA value during the first 1,2,3,5,7 days after admission was determined as D1, D2, D3, D5, D7 TBA max. Patients were divided into the high TBA (HTBA) group and the normal TBA (NTBA) group according to whether the TBA max was ≥10 μmol/L. The prognosis and complications, including death, organ failure (OF) and pancreatic necrosis, were compared between the two groups. Logistic regression analysis and receiving operating characteristic (ROC) curve were used to evaluate the relationship between circulating TBA and organ failure in AP patients. Results: Through stratified analysis of each time period, we found that the incidence of OF in the HTBA group was significantly higher than that in the NTBA group, and the AP severity classification in the HTBA group was more serious than that in the NTBA group. In addition, according to the D7 TBA max values, the pancreatic necrosis rate, percutaneous catheter drainage (PCD) rate and mortality in the HTBA group were higher than those in the NTBA group. Multivariate regression analysis showed that HTBA (odds ratio (OR), 4.894; P = 0.002) was an independent risk factor for AP complicated with OF, which was verified in the grouping based on D7 TBA max. ROC analysis revealed that a circulating D7 TBA max cutoff point of 6.450 umol/L had optimal predictive value for the development of OF in AP patients with an area under the curve of the ROC curve (AUCROC) of 0.777. Conclusions: The increase of circulating TBA in early stage of AP is independently related to organ failure, which indicates the adverse prognosis of AP patients.

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The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis

Cited by 25 publications

References 46 publications

RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis

RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

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