CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth

Crozier, Stephen J.; Sans, Maria Dolors; Wang, Jackie Y.; Lentz, Stephen I.; Ernst, Stephen A.; Williams, John A.

doi:10.1152/ajpgi.00445.2009

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…As a CK2 flavonoid inhibitor, luteolin decreases the phosphorylation of serine residues and influences processes such as transcriptional regulation and signal transduction in cells[37], [38]. Consistent with previous studies, we found that pre-treatment with luteolin reduced the ΔFosB protein level in the CPu and the locomotor activity of mice sensitized by MA.…”

Section: Discussionsupporting

confidence: 91%

Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice

et al. 2014

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GoalTo investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogen-activated protein kinase (MAPK) signal transduction pathway activation in mice.MethodsMice received a single dose of MA to induce hyperactivity or repeated intermittent intraperitoneal injections of MA to establish an MA-induced behavioral sensitization mouse model. The effect of luteolin on the development and expression of MA-induced hyperactivity and behavioral sensitization was examined. The expression and activity of ΔFosB and the levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), phosphorylated c-Jun N-terminal kinase (pJNK), and phosphorylated p38 mitogen-activated protein kinase (pp38) in the caudate putamen (CPu) were measured by western blot.ResultsLuteolin significantly decreased hyperactivity as well as the development and expression of MA-induced behavioral sensitization in mice. ΔFosB, pERK1/2, and pJNK levels in the CPu were higher in MA-treated mice than in control mice, whereas the pp38 level did not change. Injection of luteolin inhibited the MA-induced increase in ΔFosB, pERK1/2, and pJNK levels, but did not affect the pp38 level.ConclusionsLuteolin inhibits MA-induced hyperactivity and behavioral sensitization in mice through the ERK1/2/ΔFosB pathway. Furthermore, the JNK signaling pathway might be involved in MA-induced neurodegeneration in the CPu, and luteolin inhibits this process.

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Section: Discussionsupporting

confidence: 91%

Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice

et al. 2014

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“…2A and B). We next queried whether endogenous GLP-1R signaling was required for the adaptive increase in pancreatic mass in response to an HPD (20); however, pancreas weight was increased to a similar extent in HPD-fed Glp1r +/+ versus Glp1r 2/2 mice (Fig. 2C).…”

Section: Resultsmentioning

confidence: 99%

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

et al. 2014

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Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R–dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R–dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

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“…A high-protein (40%) diet can induce pancreas growth in mice, independent of cholecystokinin (CCK). 39 Other studies have shown that AAs can increase pancreatic trypsin levels and stimulate pancreas growth, 40 , 41 and the AA leucine, specifically, modulates growth responses of pancreatic progenitors, involving mTORC1. 42 , 43…”

mentioning

confidence: 98%

Dietary Protein and Amino Acid Deficiency Inhibit Pancreatic Digestive Enzyme mRNA Translation by Multiple Mechanisms

Sans

Crozier

Vogel

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Chronic amino acid (AA) deficiency, as in kwashiorkor, reduces the size of the pancreas through an effect on mammalian target of rapamycin complex 1 (mTORC1). Because of the physiological importance of AAs and their role as a substrate, a stimulant of mTORC1, and protein synthesis, we studied the effect of acute protein and AA deficiency on the response to feeding. Methods ICR/CD-1 mice were fasted overnight and refed for 2 hours with 4 different isocaloric diets: control (20% Prot); Protein-free (0% Prot); control (AA-based diet), and a leucine-free (No Leu). Protein synthesis, polysomal profiling, and the activation of several protein translation factors were analyzed in pancreas samples. Results All diets stimulated the Protein Kinase-B (Akt)/mTORC1 pathway, increasing the phosphorylation of the kinase Akt, the ribosomal protein S6 (S6) and the formation of the eukaryotic initiation factor 4F (eIF4F) complex. Total protein synthesis and polysome formation were inhibited in the 0% Prot and No Leu groups to a similar extent, compared with the 20% Prot group. The 0% Prot diet partially reduced the Akt/mTORC1 pathway and the activity of the guanine nucleotide exchange factor eIF2B, without affecting eIF2α phosphorylation. The No Leu diet increased the phosphorylation of eIF2α and general control nonderepressible 2, and also inhibited eIF2B activity, without affecting mTORC1. Essential and nonessential AA levels in plasma and pancreas indicated a complex regulation of their cellular transport mechanisms and their specific effect on the synthesis of digestive enzymes. Conclusions These studies show that dietary AAs are important regulators of postprandial digestive enzyme synthesis, and their deficiency could induce pancreatic insufficiency and malnutrition.

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CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth

Cited by 15 publications

References 36 publications

Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice

Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

Dietary Protein and Amino Acid Deficiency Inhibit Pancreatic Digestive Enzyme mRNA Translation by Multiple Mechanisms

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