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
Abstract
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.

Keywords: Acute pancreatitis, Amino acid transporter, LAT1, Metabolism, Regeneration, Fibrosis

Core Tip: LAT1 (slc7a5) transports amino acids into cells and is an upstream regulator of metabolic signaling pathways. This transporter was shown to play an important role in highly proliferative cells during embryonic development and cancer, controlling protein synthesis and cell proliferation. In this study we provide evidence that LAT1 plays a role in the pancreatic acinar regeneration after acute pancreatitis. Additionally, knocking down LAT1 revealed a sex difference in the regenerative process, which may be supportive to understand gender differences in the clinical setting.