Leucine stimulates procollagen alpha1(I) translation on hepatic stellate cells through ERK and PI3K/Akt/mTOR activation.
The essential amino acid leucine has been described to specifically activate signaling pathways leading to the activation of the translational machinery and the increase of total protein synthesis. Regulation of type I collagen production by hepatic stellate cells (HSC) is a multistep process involving transcriptional and post-transcriptional mechanisms. In the present work we studied the effect of leucine on translation regulation of collagen alpha1(I) production in HSC and the signaling pathways involved. Treatment of HSC with 5 mM leucine did not alter half-life or steady state levels of procollagen alpha1(I) mRNA, but caused an increase in procollagen alpha1(I) protein that correlated with changes of components involved in translational regulation, like enhanced 4E-BP1, Mnk-1, and eIF4E phosphorylation. Leucine also induced mTOR, ERK, and Akt phosphorylation in HSC, without affecting p38 and JNK activation. Pre-treatment of HSC with PD098059, wortmannin, or rapamycin prevented the profibrogenic action of leucine due to the inhibition of different molecular mechanisms. These results suggest leucine is a profibrogenic agent for HSC, activating signaling pathways that lead to an enhancement of collagen alpha1(I) production through translational regulation.
Pérez de Obanos
María P
MP
Departamento de Bioquímica y Biología Molecular, Universidad de Navarra, Pamplona, Navarra, Spain.
López Zabalza
María J
MJ
Prieto
Jesús
J
Herraiz
María T
MT
Iraburu
María J
MJ
D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D000090602:Collagen Type I, alpha 1 Chain; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007930:Leucine / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014633:Valine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007930:Leucine; D014633:Valine