title: The role of TRIB1 in lipid metabolism; from genetics to pathways.
abstract: The plasma concentration of lipids is a heritable risk factor for the development of atherosclerosis and related coronary artery diseases (CAD). Mammalian tribbles homologue 1 (TRIB1) is a human locus, the downstream linkage disequilibrium (LD) block of which affects plasma low-density lipoprotein (LDL)-associated cholesterol, triglyceride (TG) levels and CAD across multiple ethnic groups. In addition, association of TRIB1 with non-alcoholic fatty liver disease (NAFLD) has also been shown. A regulatory sequence that enhances TRIB1 promoter activity was identified in the LD block and the minor allele of a single nt polymorphism (SNP, rs6982502) in this regulatory sequence reduces the activity of the TRIB1 promoter. The minor allele of rs6982502 is a risk allele for increasing plasma lipid levels and NAFLD. Trib1 deficiency increases plasma cholesterol and TGs in mice and overexpression of TRIB1 in mouse liver reduces these factors. Expression of rate-limiting lipogenic enzymes is increased in Trib1-knockout mouse liver and decreased with overexpression. Recently, carbohydrate-responsive element-binding protein (ChREBP) emerged as a novel binding partner of TRIB1. Furthermore, novel binding partner, Sin3A (Swi-independent 3A)-associated protein, 18 kDa, was identified, which activates microsomal TG transfer protein (MTTP) expression by binding with MTTP regulatory elements in co-ordination with mSin3A and TRIB1. Very recently, a small molecular compound that up-regulates TRIB1 expression in HepG2 cells has been discovered. Further exploration of the binding partners of TRIB1 and their involvement in lipid metabolism may aid discovery of novel pharmacological targets for the management of dyslipidaemia and steatosis.
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan siwamoto@jichi.ac.jp.
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Supichaya
authors.initials: S
authors.lastname: Boonvisut
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Saho
authors.initials: S
authors.lastname: Makishima
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yuumi
authors.initials: Y
authors.lastname: Ishizuka
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood; D051379:Mice; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: lipid transfer protein; molecular interaction; single nucleotide polymorphism (SNP) association studies; triglyceride; very low-density lipoprotein (VLDL)