Abstract
Recent genome-wide association studies have identified a genetic locus at human chromosome 8q24 as having minor alleles associated with lower levels of plasma triglyceride (TG) and LDL cholesterol (LDL-C), higher levels of HDL-C, as well as decreased risk for myocardial infarction. This locus contains only one annotated gene, tribbles homolog 1 (TRIB1), which has not previously been implicated in lipoprotein metabolism. Here we demonstrate a role for Trib1 as a regulator of lipoprotein metabolism in mice. Hepatic-specific overexpression of Trib1 reduced levels of plasma TG and cholesterol by reducing VLDL production; conversely, Trib1-knockout mice showed elevated levels of plasma TG and cholesterol due to increased VLDL production. Hepatic Trib1 expression was inversely associated with the expression of key lipogenic genes and measures of lipogenesis. Thus, we provide functional evidence for what we believe to be a novel gene regulating hepatic lipogenesis and VLDL production in mice that influences plasma lipids and risk for myocardial infarction in humans.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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APOBEC-1 Deaminase
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Animals
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Cytidine Deaminase / deficiency
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Cytidine Deaminase / genetics
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Gene Expression
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Humans
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Lipid Metabolism / genetics*
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Lipogenesis / genetics
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Lipoproteins, VLDL / biosynthesis
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Liver / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myocardial Infarction / genetics*
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Myocardial Infarction / metabolism
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
Substances
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Intracellular Signaling Peptides and Proteins
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Lipoproteins, VLDL
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RNA, Messenger
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Receptors, LDL
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Trib1 protein, mouse
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Protein Serine-Threonine Kinases
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APOBEC-1 Deaminase
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APOBEC1 protein, human
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Apobec1 protein, mouse
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Cytidine Deaminase