title: ERK1/2 regulates hepatocyte Trib1 in response to mitochondrial dysfunction.
abstract: The TRIB1 locus (8q24.13) is a novel locus identified and replicated by several genome-wide association studies for associations with plasma triglycerides, apolipoprotein B and coronary artery disease. The TRIB1 protein product, tribbles-like protein 1 (Trib1), regulates MAPK activity. MAP kinases transduce a large variety of external signals, leading to a wide range of cellular responses, including growth, differentiation, inflammation and apoptosis. Importantly, Trib1 has been shown to regulate hepatic lipogenesis and very low density lipoprotein production. Despite the relevance of hepatocyte Trib1 to lipid metabolism and atherosclerosis, little is known about the mechanisms regulating Trib1 itself. Here, we identify the mitochondria axis as a regulator of Trib1. Treatment of HepG2 cells with a short pulse of a low oligomycin concentration led to a potent and prolonged increase in the Trib1 mRNA, an effect that was shared with other mitochondria stressors. HuH7 cells as well murine hepatocytes were also responsive albeit to a weaker extent. The upregulation appeared largely independent of reactive oxygen species generation or metabolic stress and was mainly under transcriptional control, with ERK1/2 playing an important regulating role in the process. While the presence of the Trib1 protein could be inferred, attempts to correlate the increased mRNA to changes in protein level were unsuccessful due to the lack of recognizable Trib1 signal. Our data enrich the current paradigm of Trib1 as an activator of the MAPK pathway by uncovering a role for MAPK in regulating Trib1.
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Soubeyrand
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Thet
authors.initials: T
authors.lastname: Naing
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Martinuk
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada; Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address: rmcpherson@ottawaheart.ca.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
mesh_terms: D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D000939:Epitopes; D047908:Intracellular Signaling Peptides and Proteins; D009840:Oligomycins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases
keywords: CAD; ERK1/2; GWAS; HepG2; Hepatocytes; MAPK; Mitochondria; OLGM; Oligomycin; TRIB1; VLDL; coronary artery disease; extracellular signal-regulated kinase 1/2; genome-wide association study; mitogen-activated protein kinase; oligomycin A; tribbles homolog 1; very low density lipoprotein