Abstract
The functional relationship between bile acid (BA) and autophagy has not been evaluated in the context of pancreatitis. Here we investigated whether BA and their nuclear farnesoid X receptor (FXR) modulate autophagy and the development of pancreatitis. FXR expression, autophagy, apoptosis and necroptosis were determined in human chronic pancreatitis (CP) tissue in vivo and in pancreatic cells lines in vitro by means of real-time PCR, immunoblots and immunofluorescence. Pancreatic cell lines exposed to the most abundant BAs glycochenodeoxycholate (GCDC) and taurocholic acid (TCA) increased the expression of nuclear FXR and diminished that of the essential autophagy-related protein ATG7. BA was also elevated in pancreatic tissues from CP patients, correlating with elevated FXR and curtailed ATG7 expression with locally reduced autophagic activity. This was accompanied by an increased manifestation of CP hallmarks including apoptosis, necroptosis, inflammation and fibrosis. The present results suggest a cascade of events in which local accumulation of BA signals via FXR to suppress autophagy in pancreatic acinar cells, thereby unleashing acinar cell apoptosis and necroptosis. Thus, BA may cause CP by suppressing autophagy and exacerbating acinar cell apoptosis and necroptosis.
Highlights
The nuclear bile acid receptor, known as farnesoid X receptor (FXR), plays an essential role in regulating the metabolism of BAs, lipids and glucose.[1,2] nutritional and energy homeostasis is largely influenced by the evolutionarily conserved autophagy pathway.[3,4] Activation of FXR can suppress the activation of autophagy by diminishing the expression of several autophagyrelated genes such as Atg[7] and Lamp-2,5–7 suggesting a link between BA, their action on FXR, autophagy and metabolic regulation
Normalized ΔΔCT values of Atg[7] mRNA expression were plotted as means ± S.E.M. for the numbers of experiments indicated in the graphs. *Po0.05; ***Po0.001; 20 × objective; scale bar = 20 μm
Quantitative real-time PCR of human MIA PaCa-2 (Supplementary Figure B) and rat acinar-like AR42J cells (Supplementary Figure C) revealed an increase of Fxr mRNA and a decrease of Atg[7] and Atg[5] mRNA in response to GCDC, confirming our results. These data indicate that BA facilitate the expression and/or nuclear translocation of FXR and suppress the transcription of ATG7 in pancreatic acinar cells, confirming similar findings in hepatocytes.[3,6]
Summary
The nuclear bile acid receptor, known as farnesoid X receptor (FXR), plays an essential role in regulating the metabolism of BAs, lipids and glucose.[1,2] nutritional and energy homeostasis is largely influenced by the evolutionarily conserved autophagy pathway.[3,4] Activation of FXR can suppress the activation of autophagy by diminishing the expression of several autophagyrelated genes such as Atg[7] and Lamp-2,5–7 suggesting a link between BA, their action on FXR, autophagy and metabolic regulation. Autophagy is activated under cellular stress or upon energy depletion in order to sequester cytoplasmic components for their degradation/recycling and energy generation.[8,9] Pancreatic acinar cells are highly efficient in synthesizing and releasing digestive enzymes, meaning that they are continuously exposed to high levels of misfolded or denatured proteins with potentially toxic functions. Disabled autophagy has been linked to multiple distinct pathologies including inflammatory diseases such as pancreatitis.[9,10,11] depletion of pancreatic Atg[7] or Atg[5] (which both are essential for the autophagic process) can induce acinar cell death, thereby triggering acute pancreatitis (AP) and later chronic pancreatitis (CP).[10,12,13]
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