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.
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October 2015
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Review Article|
October 09 2015
The role of TRIB1 in lipid metabolism; from genetics to pathways
Sadahiko Iwamoto;
Sadahiko Iwamoto
1
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
1To whom correspondence should be addressed (emailsiwamoto@jichi.ac.jp).
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Supichaya Boonvisut;
Supichaya Boonvisut
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
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Saho Makishima;
Saho Makishima
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
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Yuumi Ishizuka;
Yuumi Ishizuka
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
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Kazuhisa Watanabe;
Kazuhisa Watanabe
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
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Kazuhiro Nakayama
Kazuhiro Nakayama
*Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
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Publisher: Portland Press Ltd
Received:
April 28 2015
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2015 Authors; published by Portland Press Limited
2015
Biochem Soc Trans (2015) 43 (5): 1063–1068.
Article history
Received:
April 28 2015
Citation
Sadahiko Iwamoto, Supichaya Boonvisut, Saho Makishima, Yuumi Ishizuka, Kazuhisa Watanabe, Kazuhiro Nakayama; The role of TRIB1 in lipid metabolism; from genetics to pathways. Biochem Soc Trans 1 October 2015; 43 (5): 1063–1068. doi: https://doi.org/10.1042/BST20150094
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