L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases

Abstract

We studied the mechanisms by which L-glutamine (Gln), a major fuel for enterocytes, signals proliferation in intestinal epithelial cell lines. Gln was additive to epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) in stimulating DNA synthesis, as assessed by [3H]thymidine incorporation. Extracellular signal-regulated kinases (ERKs) p42mapk and p44mapk and Jun nuclear kinases (JNKs) phosphorylate and activate nuclear transcription factors. Proteins of the c-Jun, ATF-2, and c-Fos families aggregate to form DNA-binding homodimers or heterodimers called activating protein 1 (AP-1). In vitro assays and functional assays of phosphorylation demonstrated that Gln activates both ERKs and JNKs, resulting in a fourfold increase in AP-1-dependent gene transcription. Gln was required for EGF signaling through ERKs. Maximal stimulation of proliferation required approximately 2.5 mM Gln. c-Jun mRNA levels responded to Gln in "Gln-starved" porcine IPEC-J2 cells and in rat IEC-6 cells. Although Gln metabolism is required for the proliferative response, several Gln by-products did not stimulate [3H]thymidine incorporation, with the exception of arginine. Gln may be a unique nutrient for enterocytes, capable of dual signaling and augmenting the effects of growth factors that govern cellular proliferation and repair.

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

“…Among amino acids, glutamine, which is the most abundant circulating amino acid, stimulates or inhibits the expression of various genes. This includes (i) intracellular proteins such as transcription factors (3,4), constitutive proteins of the cytoskeleton (5,6) and of the extracellular matrix (7), heat shock proteins (8) or metabolic enzymes (9,10); (ii) membrane proteins such as the transport system (11); and (iii) secreted proteins such as acute phase proteins (12), cytokines (13,14), and growth factor (15). However, the molecular mechanism(s) involved in the glutamine effect is not totally understood and may depend on the cell type studied.…”

“…However, the molecular mechanism(s) involved in the glutamine effect is not totally understood and may depend on the cell type studied. For example, glutamine metabolism was involved in the stimulation of phosphoenolpyruvate carboxykinase gene expression in isolated rat hepatocytes (16) and c-jun gene expression in enterocytes (3), but amino acid-induced cell swelling was also identified as the inducing pathway on gene expression in hepatocytes (5,6). Moreover, studying the regulation of the expression of argininosuccinate synthetase (ASS) 1 (EC 6.3.4.5.…”

Mammalian Target of Rapamycin and Protein Kinase A Signaling Mediate the Cardiac Transcriptional Response to Glutamine

“…Recent studies indicate that glutamine is a major gluconeogenic precursor and vehicle for interorgan carbon transport in man (19). It has long been known that under certain physiological circumstances glutamine serves as major fuel for the gut (20,21), the kidney (22), and the immune system (23-26). Many lines of cultured mammalian cells utilize glutamine, in preference to glucose, as their major carbon source to meet energetic and biosynthetic needs (24,25).…”

Ação trófica de aditivos fitogênicos, glutamina e ácido glutâmico sobre a Bursa de Fabrícius e intestino delgado de frangos de corte

“…Outra importante função da glutamina é a indução mecanismos de transcrição gênica pela ativação da proteína quinase, que é uma enzima que ativa mitogênese na região das criptas do epitélio intestinal, levando ao aumento da proliferação celular, influenciando na manutenção da estrutura da mucosa (Blikslager & Roberts 1997, Rhoads et al 1997. Já os aditivos fitogênicos vêm sendo estudados como suplementos eficazes na redução de infecções tanto por bacté-rias quanto por Eimerias sp.…”