PMID- 35954188
OWN - NLM
STAT- MEDLINE
DCOM- 20220815
LR  - 20221125
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 15
DP  - 2022 Jul 29
TI  - Hydrophobic Bile Salts Induce Pro-Fibrogenic Proliferation of Hepatic Stellate 
      Cells through PI3K p110 Alpha Signaling.
LID - 10.3390/cells11152344 [doi]
LID - 2344
AB  - Bile salts accumulating during cholestatic liver disease are believed to promote 
      liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces 
      expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver 
      fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We 
      aimed to characterize the effects of different bile salts on HSC biology and 
      investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated 
      with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen 
      deposition, and activation of signaling pathways were determined. Activation of 
      the human HSC cell line LX 2 was assessed by quantification of alpha-smooth muscle 
      actin (alphaSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent 
      signaling was inhibited both pharmacologically and by siRNA. CDC, the most 
      abundant bile salt accumulating in human cholestasis, but no other bile salt 
      tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC 
      proliferation and subsequent collagen deposition. Pharmacological inhibition of 
      the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic 
      proliferation of HSCs. The PI3K p110alpha-specific inhibitor Alpelisib and 
      siRNA-mediated knockdown of p110alpha ameliorated pro-fibrogenic activation of mHSC 
      and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is 
      selectively induced by CDC. PI3K p110alpha may be a potential therapeutic target for 
      the inhibition of bile salt-induced fibrogenesis in cholestasis.
FAU - Zimny, Sebastian
AU  - Zimny S
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Koob, Dennis
AU  - Koob D
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Li, Jingguo
AU  - Li J
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Wimmer, Ralf
AU  - Wimmer R
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Schiergens, Tobias
AU  - Schiergens T
AUID- ORCID: 0000-0001-6111-5328
AD  - Department of General, Visceral and Transplantation Surgery, University Hospital, 
      LMU Munich, Marchioninistr. 15, 81377 Munich, Germany.
FAU - Nagel, Jutta
AU  - Nagel J
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Reiter, Florian Paul
AU  - Reiter FP
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
AD  - Division of Hepatology, Department of Medicine II, University Hospital Wurzburg, 
      Oberdurrbacher Str. 6, 97080 Wurzburg, Germany.
FAU - Denk, Gerald
AU  - Denk G
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
FAU - Hohenester, Simon
AU  - Hohenester S
AUID- ORCID: 0000-0002-9982-6317
AD  - Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377 Munich, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220729
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
SB  - IM
MH  - Animals
MH  - Bile Acids and Salts/metabolism/pharmacology
MH  - Cell Proliferation
MH  - *Cholestasis/pathology
MH  - Collagen/metabolism
MH  - *Hepatic Stellate Cells/metabolism
MH  - Humans
MH  - Liver Cirrhosis/metabolism
MH  - Mice
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - RNA, Small Interfering/metabolism
PMC - PMC9367387
OTO - NOTNLM
OT  - Alpelisib
OT  - HSC
OT  - chenodeoxycholate
OT  - cholestasis
OT  - liver fibrosis
OT  - myofibroblast
OT  - phosphatidyl-inositol-3-kinase p110 alpha
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2022/08/13 06:00
MHDA- 2022/08/16 06:00
PMCR- 2022/07/29
CRDT- 2022/08/12 01:04
PHST- 2022/06/14 00:00 [received]
PHST- 2022/07/08 00:00 [revised]
PHST- 2022/07/26 00:00 [accepted]
PHST- 2022/08/12 01:04 [entrez]
PHST- 2022/08/13 06:00 [pubmed]
PHST- 2022/08/16 06:00 [medline]
PHST- 2022/07/29 00:00 [pmc-release]
AID - cells11152344 [pii]
AID - cells-11-02344 [pii]
AID - 10.3390/cells11152344 [doi]
PST - epublish
SO  - Cells. 2022 Jul 29;11(15):2344. doi: 10.3390/cells11152344.