Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2022; 28(10): 1024-1054
Published online Mar 14, 2022. doi: 10.3748/wjg.v28.i10.1024
Loss of LAT1 sex-dependently delays recovery after caerulein-induced acute pancreatitis
Cristina M Hagen, Eva Roth, Theresia Reding Graf, François Verrey, Rolf Graf, Anurag Gupta, Giovanni Pellegrini, Nadège Poncet, Simone Mafalda Rodrigues Camargo
Cristina M Hagen, Eva Roth, François Verrey, Nadège Poncet, Simone Mafalda Rodrigues Camargo, Institute of Physiology, University of Zurich, Zurich 8057, ZH, Switzerland
Theresia Reding Graf, Rolf Graf, Anurag Gupta, Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, Zurich University Hospital, Zurich 8091, ZH, Switzerland
Giovanni Pellegrini, Institute of Veterinary Pathology, University of Zurich, Zurich 8057, ZH, Switzerland
Author contributions: Camargo SM, Poncet N, and Hagen CM designed and coordinated the study; Hagen CM, Roth E, Reding T, Gupta A, Pellegrini G, and Camargo SM performed the experiments, acquired and analyzed data; Hagen CM, Reding T, Verrey F, Graf R, Poncet N, and Camargo SM interpreted the data; Hagen CM and Camargo SM wrote the manuscript; all authors approved of the final version of the article.
Supported by Swiss National Science Foundation, Grant No. 31_166430/1 (to Verrey F).
Institutional review board statement: The study was reviewed and approved by Professors François Verrey and Rolf Graf.
Institutional animal care and use committee statement: Animal experiments adhered to the internationally accepted principles for the care and use of laboratory animals (License ZH075/15, Zurich Cantonal Veterinary office, Switzerland).
Conflict-of-interest statement: The authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Simone Mafalda Rodrigues Camargo, PhD, Pharmacist, Senior Scientist, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, ZH, Switzerland. simone.camargo@physiol.uzh.ch
Received: August 22, 2021
Peer-review started: August 22, 2021
First decision: September 12, 2021
Revised: October 8, 2021
Accepted: January 27, 2022
Article in press: January 27, 2022
Published online: March 14, 2022
Processing time: 200 Days and 13.4 Hours
ARTICLE HIGHLIGHTS
Research background

As a highly metabolically active organ, the pancreas depends on a constant supply of amino acids to synthesize digestive enzymes and for use as an energy source. This multifunctionality is reflected in the broad range of expressed amino acid transporters (AAT). Furthermore, after acute injury, the organ is capable of regeneration. Following acute pancreatitis (AP), acinar cells change their metabolic and functional state, initially dedifferentiating, increasing proliferation, and finally restoring their secretory function. AAT that are expressed in pancreatic acinar cells might play an additional role, which involves controlling the transcription of secreted enzymes and thus influencing the course of pancreatic disease and regeneration. LAT1 works as a sensor for extracellular amino acid availability and is an upstream regulator of the mammalian target of rapamycin pathway. This transporter is overexpressed in highly proliferative cells. Additionally, our previous study showed that LAT1 is expressed in acinar cells and that LAT1 expression in the early phase of AP is maintained in a different way to other AAT.

Research motivation

Lasting pancreatic disease is often detrimental to the quality and duration of life. Despite the high incidence of AP, there are no specific treatments, yet understanding pathophysiological processes is a crucial part of enabling future studies on preventative and therapeutic options. The role of AAT in this process is not comprehensively understood. Their pattern of expression may indicate that necessary metabolic adjustments are needed to meet the requirements for regeneration and reconstitution of function, which could be used as a supportive intervention during treatment.

Research objectives

The focus of the present study was to analyze metabolic alterations in the pancreas during acute inflammation by concentrating on the role of LAT1. The degree of initial injury as well as the course of regeneration were studied to investigate the significance of LAT1.

Research methods

To investigate the role of LAT1, an inducible knockout mouse model was applied, and the course of caerulein- (cae-) induced AP was studied in line with the phases of injury through to regeneration. Moreover, we analyzed the function of acinar cells and several markers of dedifferentiation and metabolic pathways.

Research results

The absence of LAT1 did not cause more severe injury during AP, but it did alter early metabolic adaptation. Consequently, differentiation and the function of acinar cells in LAT1 knockout mice were reduced, which influenced the regeneration phase. A sex-related difference was also revealed: female mice sustained more pronounced cell dedifferentiation and fibrosis.

Research conclusions

LAT1 supports the regeneration of pancreatic acinar cells after AP via metabolic adaptation, influencing their differentiation as well as their recovery of function and phenotype. The knocking out of LAT1 had a more accentuated effect in female mice, suggesting that a sex-dependent dimorphism in AAT is present in the pancreas.

Research perspectives

Future studies should focus on the role of AAT and metabolic pathways in acinar cells by using conditional knockout models. An acinar-cell conditional knockout or overexpressing mouse model will allow us to analyze the effect of AAT, specifically in pancreatic cells, without affecting their expression in immune cells, which play an important role in the development of AP. Additionally, induction methods other than tamoxifen should be tried, and sex-dependent differences as well as the influence of age should be further considered. These models will enable a better understanding of the metabolic mechanisms, guaranteeing the survival of acinar cells after different insults.