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Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves.

ABSTRACT: As new nutritional strategies for ruminant are designed to change production efficiency by improving the supply of rumen protect protein, lipid, and even starch, the digestive system must fit to utilize these increased nutrient supplies, especially the pancreas. The objective of this study was to investigate the effects of phenylalanine (Phe) on digestive enzymes synthesis or secretion and cellular signaling in pancreatic acinar (PA) cells of dairy calves. The PA cells isolated from fresh pancreas of dairy calves, and cultured in completed RIPA 1640 medium with no fetal serum but 0, 0.15 and 0.45 mM Phe at 37°C in CO2 incubator for 120 min. The pancreatic tissue segments (PTS) was cut approximately 2 × 2 mm from the fresh pancreas, and incubated in oxygenated Krebs-Ringer bicarbonate (KRB) buffer containing 0 or 0.35 mM Phe at 39°C for 180 min, and the samples were collected every 60 min after incubation. In PA cells, Phe increased (P < 0.05) the ?-amylase secretion and mRNA expression, the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). In PTS, the Phe increased (P < 0.05) ?-amylase and trypsin synthesis, secretion and mRNA expression, as well as the phosphorylation of S6K1 and 4EBP1. Conclusively, these results suggested that Phe regulates the synthesis or secretion of ?-amylase, trypsin and lipase through mRNA translation initiation factors - S6K1 and 4EBP1.

SUBMITTER: Guo L

PROVIDER: S-EPMC5784178 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves.

Guo Long L Tian Huibin H Shen Jing J Zheng Chen C Liu Shimin S Cao Yangchun Y Cai Chuanjiang C Yao Junhu J

Bioscience reports 20180125 1

As new nutritional strategies for ruminant are designed to change production efficiency by improving the supply of rumen protect protein, lipid, and even starch, the digestive system must fit to utilize these increased nutrient supplies, especially the pancreas. The objective of this study was to investigate the effects of phenylalanine (Phe) on digestive enzymes synthesis or secretion and cellular signaling in pancreatic acinar (PA) cells of dairy calves. The PA cells isolated from fresh pancre ...[more]

PMID: 29263147

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

Dataset Information

Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves.

Publications

Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves.

Similar Datasets

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