Trib1 is a lipid- and myocardial infarction–associated gene that regulates hepatic lipogenesis and VLDL production in mice
Ralph Burkhardt, … , Jan L. Breslow, Daniel J. Rader
Ralph Burkhardt, … , Jan L. Breslow, Daniel J. Rader
Published November 15, 2010
Citation Information: J Clin Invest. 2010;120(12):4410-4414. https://doi.org/10.1172/JCI44213.
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Brief Report Genetics

Trib1 is a lipid- and myocardial infarction–associated gene that regulates hepatic lipogenesis and VLDL production in mice

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.

Authors

Ralph Burkhardt, Sue-Anne Toh, William R. Lagor, Andrew Birkeland, Michael Levin, Xiaoyu Li, Megan Robblee, Victor D. Fedorov, Masahiro Yamamoto, Takashi Satoh, Shizuo Akira, Sekar Kathiresan, Jan L. Breslow, Daniel J. Rader

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Figure 1

Hepatic Trib1 overexpression reduces plasma lipid levels in mice.

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Hepatic Trib1 overexpression reduces plasma lipid levels in mice. C5...
C57BL/6 mice (n = 5 per group) were injected with 1012 genome copies (gc) control (AAV_null) or 1010, 1011, or 1012 gc AAV_trib1. (A) Plasma cholesterol and TG levels were measured 2 weeks after injection. Plasma lipoproteins were isolated by sequential ultracentrifugation, and cholesterol (B) and TG (C) levels were determined in the VLDL, LDL, and HDL fractions. (D) Pooled plasma samples were fractionated by FPLC, and TG levels were determined in collected fractions. IDL, intermediate-density lipoprotein. (E) Effects of AAV_trib1 injection (1012 gc) on plasma total cholesterol (TC) and TG in Ldlr–/– mice and (F) LAhB-H mice (n = 6 per group). Human plasma apoB was determined in LAhB-H mice and was reduced after AAV_trib1 injection. (G) Distribution of cholesterol and TG in FPLC-fractionated plasma of AAV-injected LAhB-H mice. *P < 0.05, **P < 0.005, AAV_null versus AAV_trib1 groups.