Biliary bile acids in hepatobiliary injury – What is the link?

Fickert, Peter; Wagner, Martin

doi:10.1016/j.jhep.2017.04.026

Cited by 151 publications

(138 citation statements)

References 137 publications

(191 reference statements)

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“…A recently published landmark review about BS in hepatobiliary injury discussed that it is not yet clear why biliary BS levels may be reduced after biliary obstruction. (17) The two-photon videos and MALDI imaging of the present study support the hypothesis that the leakage through bile infarcts contributes to the decreased BS concentrations in the biliary tract.…”

Section: Discussionsupporting

confidence: 82%

“…As mechanisms of BS‐mediated hepatocyte cell death in cholestasis, both necrosis and apoptosis have been shown to play a role . The present study demonstrates rupture of the canalicular membrane as a third mechanism of hepatocyte death, followed by retroflux of BS from the canaliculus into the cytoplasm.…”

Section: Discussionmentioning

confidence: 50%

“…In addition, up‐regulation of the basolateral BS export carriers MRP3 and MRP4 occurs with the reverse transport of BS from hepatocytes to blood . Leakage of BS into and from bile infarcts may represent a plausible additional fourth mechanism . Leakage through tight junctions was not observed in this study.…”

Section: Discussionmentioning

confidence: 66%

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Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood

et al. 2018

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Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so-called bile infarcts that correspond to Charcot-Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon-based imaging of BDL mice was performed with fluorescent bile salts (BS) and non-BS organic anion analogues. Key findings were followed up by matrix-assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1-3 days after BDL, BS concentrations in bile increased and single-cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a "domino effect" of further death events of neighboring hepatocytes. Bile infarcts provided a trans-epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS-overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 50%

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Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood

et al. 2018

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“…The complex pool of bile acids is then reabsorbed in the portal circulation via a large panel of transporters. In addition, bile acids are signalling molecules involved in regulating hepatic metabolism, inflammation, and their own synthesis through the activation of various nuclear receptors, such as the farnesoid X receptor (FXR) …”

Section: Introductionmentioning

confidence: 99%

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

Ciocan

Voican

Wrzosek

et al. 2018

Aliment Pharmacol Ther

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“…Bile acid effects may not only be mediated by signal cascades related to specific receptor activation but may also induce the inflammasome or be the simple consequence of toxicity or cell damage . We, therefore, correlated our in vivo findings with in vitro studies performed in H295R cells to investigate whether our results can experimentally be nailed down to direct effects of bile acids on the adrenal glands.…”

Section: Discussionmentioning

confidence: 92%

Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF‐1

Liu

Panzitt

Racedo

et al. 2019

Liver International

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Background and AimsBile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein‐coupled bile acid receptor (TGR5) and the sphingosine‐1‐phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.Methods FXR and TGR5 knockout mice and controls were subjected to common bile duct ligation (CBDL) or chenodeoxycholic acid (CDCA) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies.ResultsWe found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis‐related enzymes in adrenals independent of FXR and TGR5. Taurine‐conjugated CDCA (TCDCA) significantly stimulated cortisol secretion, phosphorylation of extracellular signal‐regulated kinase (ERK) and expression of steroidogenesis‐related genes in human adrenocortical H295R cells. FXR and TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA‐induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis‐related genes in H295R cells. Likewise, siRNA S1PR2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor‐1 (SF‐1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF‐1. Treatment with SF‐1 inverse agonist AC45594 also reduced TCDCA‐induced steroidogenesis.ConclusionsOur findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2‐ERK‐SF‐1 signalling pathway.

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Biliary bile acids in hepatobiliary injury – What is the link?

Cited by 151 publications

References 137 publications

Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood

Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF‐1

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