TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes
Katherine Quiroz-Figueroa, … , Nicholas J. Hand, Daniel J. Rader
Katherine Quiroz-Figueroa, … , Nicholas J. Hand, Daniel J. Rader
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e146775. https://doi.org/10.1172/JCI146775.
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TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes

Abstract

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.

Authors

Katherine Quiroz-Figueroa, Cecilia Vitali, Donna M. Conlon, John S. Millar, John W. Tobias, Robert C. Bauer, Nicholas J. Hand, Daniel J. Rader

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Figure 6

Pathway analysis suggests that increased ATF3 contributes to the reduction in LDLR in Trib1Δhep mouse liver.

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Pathway analysis suggests that increased ATF3 contributes to the reducti...
(A) Ingenuity pathway analysis (IPA) of all predicted liver-expressed ligand-dependent nuclear receptors, transcription factors, and transcriptional regulators upstream of Ldlr (based on IPA knowledge base) overlaid with color-coded mouse liver RNA-Seq data from the comparison of Trib1Δhep transcript abundance to control. Analysis was performed on total liver RNA from chow-fed mice 4 weeks after AAV8-TBG-Cre injection (n = 6). (B) Hepatic transcript levels of ATF3 in chow-fed male mice (n = 6 per group) 4 weeks after injection AAV8-TBG-Cre. (C) Immunoblot of hepatic ATF3 and β-actin, replicated in 3 independent cohorts. (D) Motif enrichment analysis of CEBPα ChIP-seq in Trib1Δhep liver shows significant enrichment of ATF proteins. (B) Box plots indicate median and 25th and 75th percentiles, with whiskers extending to minimum and maximum values. Symbols indicate individual values. Data are expressed as mean ± SEM for the experimental group. Significance was determined by 1-way ANOVA with Tukey’s multiple comparison test (****P ≤ 0.0001).