PMID- 35431492
OWN - NLM
STAT- MEDLINE
DCOM- 20220419
LR  - 20220531
IS  - 2219-2840 (Electronic)
IS  - 1007-9327 (Print)
IS  - 1007-9327 (Linking)
VI  - 28
IP  - 10
DP  - 2022 Mar 14
TI  - Loss of LAT1 sex-dependently delays recovery after caerulein-induced acute 
      pancreatitis.
PG  - 1024-1054
LID - 10.3748/wjg.v28.i10.1024 [doi]
AB  - BACKGROUND: The expression of amino acid transporters is known to vary during 
      acute pancreatitis (AP) except for LAT1 (slc7a5), the expression of which remains 
      stable. LAT1 supports cell growth by importing leucine and thereby stimulates 
      mammalian target of rapamycin (mTOR) activity, a phenomenon often observed in 
      cancer cells. The mechanisms by which LAT1 influences physiological and 
      pathophysiological processes and affects disease progression in the pancreas are 
      not yet known. AIM: To evaluate the role of LAT1 in the development of and 
      recovery from AP. METHODS: AP was induced with caerulein (cae) injections in 
      female and male mice expressing LAT1 or after its knockout (LAT1 Cre/LoxP). The 
      development of the initial AP injury and its recovery were followed for seven 
      days after cae injections by daily measuring body weight, assessing microscopical 
      tissue architecture, mRNA and protein expression, protein synthesis, and enzyme 
      activity levels, as well as by testing the recruitment of immune cells by FACS 
      and ELISA. RESULTS: The initial injury, evaluated by measurements of plasma 
      amylase, lipase, and trypsin activity, as well as the gene expression of 
      dedifferentiation markers, did not differ between the groups. However, early 
      metabolic adaptations that support regeneration at later stages were blunted in 
      LAT1 knockout mice. Especially in females, we observed less mTOR reactivation and 
      dysfunctional autophagy. The later regeneration phase was clearly delayed in 
      female LAT1 knockout mice, which did not regain normal expression of the 
      pancreas-specific differentiation markers recombining binding protein suppressor 
      of hairless-like protein (rbpjl) and basic helix-loop-helix family member A15 
      (mist1). Amylase mRNA and protein levels remained lower, and, strikingly, female 
      LAT1 knockout mice presented signs of fibrosis lasting until day seven. In 
      contrast, pancreas morphology had returned to normal in wild-type littermates. 
      CONCLUSION: LAT1 supports the regeneration of acinar cells after AP. Female mice 
      lacking LAT1 exhibited more pronounced alterations than male mice, indicating a 
      sexual dimorphism of amino acid metabolism.
CI  - (c)The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights 
      reserved.
FAU - Hagen, Cristina M
AU  - Hagen CM
AD  - Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland.
FAU - Roth, Eva
AU  - Roth E
AD  - Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland.
FAU - Graf, Theresia Reding
AU  - Graf TR
AD  - Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation 
      Surgery, Zurich University Hospital, Zurich 8091, ZH, Switzerland.
FAU - Verrey, Francois
AU  - Verrey F
AD  - Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland.
FAU - Graf, Rolf
AU  - Graf R
AD  - Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation 
      Surgery, Zurich University Hospital, Zurich 8091, ZH, Switzerland.
FAU - Gupta, Anurag
AU  - Gupta A
AD  - Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation 
      Surgery, Zurich University Hospital, Zurich 8091, ZH, Switzerland.
FAU - Pellegrini, Giovanni
AU  - Pellegrini G
AD  - Institute of Veterinary Pathology, University of Zurich, Zurich 8057, ZH, 
      Switzerland.
FAU - Poncet, Nadege
AU  - Poncet N
AD  - Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland.
FAU - Camargo, Simone Mafalda Rodrigues
AU  - Camargo SMR
AD  - Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland. 
      simone.camargo@physiol.uzh.ch.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - World J Gastroenterol
JT  - World journal of gastroenterology
JID - 100883448
RN  - 0 (Large Neutral Amino Acid-Transporter 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (SLC7A5 protein, human)
RN  - 888Y08971B (Ceruletide)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.2.1.- (Amylases)
SB  - IM
MH  - Acute Disease
MH  - Amylases
MH  - Animals
MH  - *Ceruletide/toxicity
MH  - Female
MH  - Large Neutral Amino Acid-Transporter 1/genetics
MH  - Male
MH  - Mammals/genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Pancreas/metabolism
MH  - *Pancreatitis/chemically induced/genetics/metabolism
MH  - RNA, Messenger
MH  - TOR Serine-Threonine Kinases
PMC - PMC8968515
OTO - NOTNLM
OT  - Acute pancreatitis
OT  - Amino acid transporter
OT  - Fibrosis
OT  - LAT1
OT  - Metabolism
OT  - Regeneration
COIS- Conflict-of-interest statement: The authors have nothing to disclose.
EDAT- 2022/04/19 06:00
MHDA- 2022/04/20 06:00
PMCR- 2022/03/14
CRDT- 2022/04/18 06:31
PHST- 2021/08/22 00:00 [received]
PHST- 2021/10/08 00:00 [revised]
PHST- 2022/01/27 00:00 [accepted]
PHST- 2022/04/18 06:31 [entrez]
PHST- 2022/04/19 06:00 [pubmed]
PHST- 2022/04/20 06:00 [medline]
PHST- 2022/03/14 00:00 [pmc-release]
AID - 10.3748/wjg.v28.i10.1024 [doi]
PST - ppublish
SO  - World J Gastroenterol. 2022 Mar 14;28(10):1024-1054. doi: 
      10.3748/wjg.v28.i10.1024.