Exocrine pancreas glutamate secretion help to sustain enterocyte nutritional needs under protein restriction

Abstract

Glutamine (Gln) is the most concentrated amino acid in blood and considered conditionally essential. Its requirement is increased during physiological stress, such as malnutrition or illness, despite its production by muscle and other organs. In the malnourished state, Gln has been suggested to have a trophic effect on the exocrine pancreas and small intestine. However, the Gln transport capacity, the functional relationship of these two organs, and the potential role of the Gln-glutamate (Glu) cycle are unknown. We observed that pancreatic acinar cells express lower levels of Glu than Gln transporters. Consistent with this expression pattern, the rate of Glu influx into acinar cells was approximately sixfold lower than that of Gln. During protein restriction, acinar cell glutaminase expression was increased and Gln accumulation was maintained. Moreover, Glu secretion by acinar cells into pancreatic juice and thus into the lumen of the small intestine was maintained. In the intestinal lumen, Glu absorption was preserved and Glu dehydrogenase expression was augmented, potentially providing the substrates for increasing energy production via the TCA cycle. Our findings suggest that one mechanism by which Gln exerts a positive effect on exocrine pancreas and small intestine involves the Gln metabolism in acinar cells and the secretion of Glu into the small intestine lumen. The exocrine pancreas acinar cells not only avidly accumulate Gln but metabolize Gln to generate energy and to synthesize Glu for secretion in the pancreatic juice. Secreted Glu is suggested to play an important role during malnourishment in sustaining small intestinal homeostasis. NEW & NOTEWORTHY Glutamine (Gln) has been suggested to have a trophic effect on exocrine pancreas and small intestine in malnourished states, but the mechanism is unknown. In this study, we suggest that this trophic effect derives from an interorgan relationship between exocrine pancreas and small intestine for Gln-glutamate (Glu) utilization involving the uptake and metabolism of Gln in acinar cells and secretion of Glu into the lumen of the small intestine.

Intestinal IMINO transporter SIT1 is not expressed in human newborns

“…Even when an adequate amount of calories is supplied in the blood, as for instance with parenteral nutrition, morphological and functional alterations of the small intestine mucosa are observed; the small intestine absorptive surface area appears to be reduced because of a decrease in cell proliferation, differentiation, and migration along the crypt-to-villi axis. That luminal amino acid availability also affects intestinal amino acid transporter expression has been shown in different animal models (2,20,27,28). In our study, we observed a reduction in cryptal cell proliferation in the intestinal area distal to the obstruction not receiving amniotic fluid.…”

The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells

“…Importantly, acinar cells have great metabolic plasticity as indicated by their ability to accumulate glutamine to be metabolized into the TCA cycle for energy generation and to synthesize glutamate for secretion despite severe protein restriction in vitro and in vivo. Notably, under these experimental conditions, both GLS and GDH are transcriptionally enhanced to participate in acinar cell metabolic regulation [32]. In PDE cells, the function and subcellular distribution of mitochondria are not well characterized.…”

“…Other evidence of the important roles of mitochondria in pancreatic acinar cells is apparent from the observation that these cells rapidly accumulate glutamine in the cytoplasm [30,31], which is used in part for further substrate channeling into the TCA cycle and in part to synthesize glutamate that has been secreted in the pancreatic juice. In this regard, acinar cells express high levels of glutaminase (GLS) and glutamic dehydrogenase (GDH) enzymes, which are both required for glutamate synthesis and to produce TCA cycle substrates [32]. Importantly, acinar cells have great metabolic plasticity as indicated by their ability to accumulate glutamine to be metabolized into the TCA cycle for energy generation and to synthesize glutamate for secretion despite severe protein restriction in vitro and in vivo.…”

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

“…Reverse transcription was performed according to the manufacturer's instructions, and 10 ng cDNA was added to Taq-Man Universal PCR master mix (Applied Biosystems) using a Prism 7700 cycler (Applied Biosystems, Foster City, CA, United States). The primers and probes used in this study not yet published[ 16 , 17 , 30 , 31 ] are listed in Table 3 .…”

“…Amino acids are actively transported into acinar cells to provide the necessary building blocks for protein synthesis. An influence on amino acid transporters (AAT) by diet[ 16 ] and early AP injury[ 17 ] has been shown in our previous work. We identified the localization of the glutamine and neutral amino acid transporters LAT1 ( slc7a5 ), LAT2 ( slc7a2 ), SNAT3 ( slc38a3 ), and SNAT5 ( slc38a5 ) at the basolateral membrane of acinar cells.…”