title: Role of Tribbles Pseudokinase 1 (TRIB1) in human hepatocyte metabolism.
abstract: Genome-wide association studies for plasma triglycerides and hepatic steatosis identified a risk locus on chromosome 8q24 close to the TRIB1 gene, encoding Tribbles Pseudokinase 1 (TRIB1). In previous studies conducted in murine models, hepatic over-expression of Trib1 was shown to increase fatty acid oxidation and decrease triglyceride synthesis whereas Trib1 knockdown mice exhibited hypertriglyceridemia. Here we have examined the impact of TRIB1 suppression in human and mouse hepatocytes. Examination of a panel of lipid regulator transcripts revealed species-specific effects, prompting us to focus on human models for the remainder of the study. Acute knockdown of TRIB1 in human primary hepatocytes resulted in decreased expression of MTTP and APOB, required for very low density lipoprotein (VLDL) assembly although particle secretion was not significantly affected. A parallel analysis performed in HepG2 revealed reduced MTTP, but not APOB, protein as a result of TRIB1 suppression. Global gene expression changes of human primary hepatocytes upon TRIB1 suppression were analyzed by clustering algorithms and found to be consistent with dysregulation of several pathways fundamental to liver function, including altered CEBPA and B transcript levels and impaired glucose handling. Indeed, TRIB1 expression in HepG2 cells was found to be inversely proportional to glucose concentration. Lastly TRIB1 downregulation in primary hepatocytes was associated with suppression of the HNF4A axis. In HepG2 cells, TRIB1 suppression resulted in reduced HNF4A protein levels while HNF4A suppression increased TRIB1 expression. Taken together these studies reveal an important role for TRIB1 in human hepatocyte biology.
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address: ssoubeyrand@ottawaheart.ca.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Soubeyrand
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.
authors.forename: Thet
authors.initials: T
authors.lastname: Naing
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Paulina
authors.initials: P
authors.lastname: Lau
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address: rmcpherson@ottawaheart.ca.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; C106092:microsomal triglyceride transfer protein; D017346:Protein Serine-Threonine Kinases
keywords: Glucose; Hepatocyte; Lipid metabolism; Steatosis; TRIB1; Tribbles