PMID- 29964040
OWN - NLM
STAT- MEDLINE
DCOM- 20181023
LR  - 20210812
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 155
IP  - 4
DP  - 2018 Oct
TI  - Dysregulated Bile Transporters and Impaired Tight Junctions During Chronic Liver 
      Injury in Mice.
PG  - 1218-1232.e24
LID - S0016-5085(18)34690-0 [pii]
LID - 10.1053/j.gastro.2018.06.048 [doi]
AB  - BACKGROUND & AIMS: Liver fibrosis, hepatocellular necrosis, inflammation, and 
      proliferation of liver progenitor cells are features of chronic liver injury. 
      Mouse models have been used to study the end-stage pathophysiology of chronic 
      liver injury. However, little is known about differences in the mechanisms of 
      liver injury among different mouse models because of our inability to visualize 
      the progression of liver injury in vivo in mice. We developed a method to 
      visualize bile transport and blood-bile barrier (BBlB) integrity in live mice. 
      METHODS: C57BL/6 mice were fed a choline-deficient, ethionine-supplemented 
      (CDE) diet or a diet containing 0.1% 3,5-diethoxycarbonyl-1, 4-dihydrocollidine 
      (DDC) for up to 4 weeks to induce chronic liver injury. We used quantitative 
      liver intravital microscopy (qLIM) for real-time assessment of bile transport and 
      BBlB integrity in the intact livers of the live mice fed the CDE, DDC, or chow 
      (control) diets. Liver tissues were collected from mice and analyzed by 
      histology, immunohistochemistry, real-time polymerase chain reaction, and 
      immunoblots. RESULTS: Mice with liver injury induced by a CDE or a DDC diet had 
      breaches in the BBlB and impaired bile secretion, observed by qLIM compared with 
      control mice. Impaired bile secretion was associated with reduced expression of 
      several tight-junction proteins (claudins 3, 5, and 7) and bile transporters 
      (NTCP, OATP1, BSEP, ABCG5, and ABCG8). A prolonged (2-week) CDE, but not DDC, 
      diet led to re-expression of tight junction proteins and bile transporters, 
      concomitant with the reestablishment of BBlB integrity and bile secretion. 
      CONCLUSIONS: We used qLIM to study chronic liver injury, induced by a 
      choline-deficient or DDC diet, in mice. Progression of chronic liver injury was 
      accompanied by loss of bile transporters and tight junction proteins.
CI  - Copyright (c) 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Pradhan-Sundd, Tirthadipa
AU  - Pradhan-Sundd T
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Vats, Ravi
AU  - Vats R
AD  - Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of 
      Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
FAU - Russell, Jacquelyn O
AU  - Russell JO
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh School 
      of Medicine and University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Singh, Sucha
AU  - Singh S
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Michael, Adeola Adebayo
AU  - Michael AA
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Molina, Laura
AU  - Molina L
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Kakar, Shelly
AU  - Kakar S
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Cornuet, Pamela
AU  - Cornuet P
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Poddar, Minakshi
AU  - Poddar M
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania.
FAU - Watkins, Simon C
AU  - Watkins SC
AD  - Center for Biologic Imaging, University of Pittsburgh School of Medicine, 
      Pittsburgh, Pennsylvania.
FAU - Nejak-Bowen, Kari N
AU  - Nejak-Bowen KN
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh School 
      of Medicine and University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Monga, Satdarshan P
AU  - Monga SP
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania; Department of Medicine, University of Pittsburgh School of 
      Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University 
      of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, 
      Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.
FAU - Sundd, Prithu
AU  - Sundd P
AD  - Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of 
      Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, 
      University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh 
      Liver Research Center, University of Pittsburgh School of Medicine and University 
      of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: 
      prs51@pitt.edu.
LA  - eng
GR  - S10 RR028478/RR/NCRR NIH HHS/United States
GR  - R01 DK116993/DK/NIDDK NIH HHS/United States
GR  - S10 OD021540/OD/NIH HHS/United States
GR  - P30 DK072506/DK/NIDDK NIH HHS/United States
GR  - R01 HL128297/HL/NHLBI NIH HHS/United States
GR  - R01 DK062277/DK/NIDDK NIH HHS/United States
GR  - R01 DK103775/DK/NIDDK NIH HHS/United States
GR  - R01 CA204586/CA/NCI NIH HHS/United States
GR  - T32 CA186873/CA/NCI NIH HHS/United States
GR  - R01 DK100287/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Video-Audio Media
DEP - 20180630
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (3,5-diethoxycarbonyl-1,4-dihydrocollidine)
RN  - 0 (Claudins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Pyridines)
RN  - WX1BN24WZT (Ethionine)
SB  - IM
MH  - Animals
MH  - Bile/*metabolism
MH  - Biological Transport
MH  - Chemical and Drug Induced Liver Injury, 
      Chronic/blood/etiology/*metabolism/pathology
MH  - Choline Deficiency/complications
MH  - Claudins/metabolism
MH  - Disease Models, Animal
MH  - Ethionine
MH  - Hepatocytes/*metabolism/pathology
MH  - Kinetics
MH  - Liver/*metabolism/pathology
MH  - Membrane Transport Proteins/*metabolism
MH  - Mice, Inbred C57BL
MH  - Permeability
MH  - Pyridines
MH  - Tight Junctions/*metabolism/pathology
PMC - PMC6174089
MID - NIHMS978722
OTO - NOTNLM
OT  - Blood Bile Barrier
OT  - Claudins
OT  - Diet-Induced Liver Injury
OT  - Hepatocyte Tight Junction
COIS- The authors have no conflict of interest to declare.
EDAT- 2018/07/03 06:00
MHDA- 2018/10/24 06:00
PMCR- 2019/10/01
CRDT- 2018/07/03 06:00
PHST- 2017/12/06 00:00 [received]
PHST- 2018/05/09 00:00 [revised]
PHST- 2018/06/24 00:00 [accepted]
PHST- 2018/07/03 06:00 [pubmed]
PHST- 2018/10/24 06:00 [medline]
PHST- 2018/07/03 06:00 [entrez]
PHST- 2019/10/01 00:00 [pmc-release]
AID - S0016-5085(18)34690-0 [pii]
AID - 10.1053/j.gastro.2018.06.048 [doi]
PST - ppublish
SO  - Gastroenterology. 2018 Oct;155(4):1218-1232.e24. doi: 
      10.1053/j.gastro.2018.06.048. Epub 2018 Jun 30.