Loss of LAT1 sex-dependently delays recovery after caerulein-induced acute pancreatitis

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.

Characterization of the interactions between Fulvic acid and Trypsin with Spectroscopic and Molecular Docking technology

“…[15] TRP is the most specific protease with an indispensable role in human physiology. [16] During the process of decomposition and absorption, drugs inevitably interact with various proteases or other crucial proteins, thereby impacting protein structure and function. To enhance drug safety further, there is an increasing focus on investigating drug-protein interactions.…”

“…Trypsin (TRP) primarily functions as a digestive enzyme in the human body, exerting inhibitory effects on the activation of chymotrypsinogen, carboxypeptidase, phospholipase, and other precursor enzymes while actively participating in enzymatic regulation [15] . TRP is the most specific protease with an indispensable role in human physiology [16] . During the process of decomposition and absorption, drugs inevitably interact with various proteases or other crucial proteins, thereby impacting protein structure and function.…”