TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes

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

doi:10.1172/jci146775

Cited by 19 publications

(18 citation statements)

References 46 publications

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“…Previous studies indicated that inhibition of Trib1 caused atherogenic dyslipidemia [8], while overexpression [6] or rescue [7] of Trib1 remodeled lipid metabolism homeostasis. Therefore, rs2954029 and rs17321515 may affect lipid levels by influencing Trib1 expression [6,9,10].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the adenovirus-mediated rescue of Trib1 expression in liver-specific Bmal1 knock-out mice lowered plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, increased low-density lipoprotein receptor (LDLR) counts, and decreased plasma LDL-C levels [7]. However, deletion of Trib1 increased CCAAT/enhancer-binding protein alpha (CEBPα) and activated transcription factor 3 (ATF3) levels, reduced LDLR counts, and elevated plasma LDL-C levels [8]. Collectively, it indicated that Trib1 protein expression was closely related to lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Effect of TRIB1 Variant on Lipid Profile and Coronary Artery Disease: A Systematic Review and Meta-Analysis

Wei

Liu

et al. 2023

Cardiovascular Therapeutics

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Background. Emerging evidence indicates tribbles homolog 1 (Trib1) protein may be involved in lipid metabolism regulation and coronary artery disease (CAD) pathogenesis. However, whether TRIB1 gene variants affect lipid levels and CAD remains elusive, this study is aimed at clarifying the effect of TRIB1 variants on lipid profile and CAD. Methods. By searching PubMed and Cochrane databases for studies published before December 18, 2022, a total of 108,831 individuals were included for the analysis. Results. The outcomes of the analysis on all individuals showed that the A allele carriers of rs17321515 and rs2954029 variants had higher low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels than the noncarriers. Consistently, a higher CAD risk was observed in the A allele carriers. Subgroup analysis indicated that increased LDL-C, TC, and CAD risk were observed in Asian population. Conclusions. Variants of TRIB1 (i.e., rs17321515 and rs2954029) may serve as causal genetic markers for dyslipidemia and CAD in Asian population.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of TRIB1 Variant on Lipid Profile and Coronary Artery Disease: A Systematic Review and Meta-Analysis

Wei

Liu

et al. 2023

Cardiovascular Therapeutics

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“…However, ATF3 was reported to lead to the transcriptional repression of LDLR in isolated human liver Sk-Hep1 cells treated with tunicamycin and oligomycin (95). Moreover, Quiroz-Figueroa et al confirmed that ATF3 mediated the impairment of hepatic LDL catabolism induced by Tribbles pseudokinase 1 (Trib1) depletion via the down-regulation of LDLR, the blunting of which reversed the level of plasma LDL cholesterol and LDLR function in Trib1Δhep mice (96). In summary, the overall role of ATF3 in hepatic lipid metabolism and dyslipidemia is yet to be fully elucidated.…”

Section: Dyslipidemiamentioning

confidence: 99%

ATF3 and its emerging role in atherosclerosis: a narrative review

Wu¹,

Zhou²,

Xiang³

et al. 2022

Cardiovasc Diagn Ther

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Background and Objective: Atherosclerosis (AS), is characterized by the subintima lipid accumulation and chronic inflammation inside the arterial wall, causing much mortality and morbidity worldwide.Activating transcription factor 3 (ATF3) is a member of ATF/cAMP-responsive element-binding (CREB) family of transcription factors, which acts as a master regulator of adaptive response. Recent studies have indicated the implicated role of ATF3 in atherogenesis and AS progression due to its impact on metabolic disorder, vascular injury, plaque formation, and stability. In this review, we summarize the current advances in the mechanism of ATF3 activation and the contribution of ATF3 in AS, highlighting vascular intrinsic and extrinsic mechanisms of how ATF3 influences the pathology of AS. Methods:The relevant literature (from origin to March 2022) was retrieved through PubMed research to explore the regulatory mechanism of ATF3 and the specific role of ATF3 in AS. Only English publications were reviewed in this paper.Key Content and Findings: ATF3 acts as a key regulator of AS progression, which not only directly affects atherosclerotic lesions by regulating vascular homeostasis, but also gets involved in AS through systemic glucolipid metabolism and inflammatory response. The two different promoters, transcript variants, and post-translational modification in distinct cell types partly contribute to the regulatory diversity of ATF3 in AS.Conclusions: ATF3 is a crucial transcription regulatory factor during atherogenesis and AS progression.Gaining a better understanding of how ATF3 affects vascular, metabolic, and immune homeostasis would advance the progress of ATF3-targeted therapy in AS.

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Section: Introductionmentioning

confidence: 99%

“…This leads to the COP1-facilitated polyubiquitination of the substrate, leading to its proteasomal degradation. Due to their roles in the regulation of transcription factors and metabolic proteins, Tribbles proteins have been variously implicated in a wide range of pathologies, particularly cancer and cardiometabolic disease (Du et al, 2003;Johnston et al, 2019;Keeshan et al, 2006Keeshan et al, , 2010Qi et al, 2006;Quiroz-Figueroa et al, 2021). TRIB1 and TRIB2 have been associated with human acute myeloid leukemia (AML) for some time (Keeshan et al, 2006;Röthlisberger et al, 2007;Rücker et al, 2006), and TRIB3 has also been recently implicated in the disease (Luo et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Nanobodies identify an activated state of the TRIB2 pseudokinase

Jamieson

Pudjihartono

Horne

et al. 2022

Preprint

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Tribbles proteins (TRIB1–3) are a pseudokinase-only branch of the human kinome, which recruit substrates to the COP1 ubiquitin-ligase for ubiquitination. TRIB2 was the first Tribbles ortholog to be implicated as a myeloid leukaemia oncogene, by way of recruiting the C/EBPa transcription factor for degradation by COP1. Here we report selection and characterisation of nanobodies against the TRIB2 pseudokinase domain from a synthetic yeast surface-display library. We identified nanobodies that bind the TRIB2 pseudokinase domain with low nanomolar affinity. A crystal structure of Nb4.103 in complex with TRIB2 identified a mode of binding to the N-terminal lobe of the pseudokinase, in a manner that enables specific recognition of TRIB2 over TRIB1 and TRIB3. In the nanobody-stabilised state, TRIB2 adopts an activated conformation that is remarkably similar to the C/EBPa-bound state of TRIB1. Characterization in solution revealed that Nb4.103 can stabilise a TRIB2 pseudokinase domain dimer in a face-to-face manner. Conversely, a distinct nanobody (Nb4.101) binds through a similar epitope but does not readily promote dimerization. In combination, this study identifies features of TRIB2 that could be exploited for the development of inhibitors, and nanobody tools for future investigation of TRIB2 function.

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TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes

Cited by 19 publications

References 46 publications

Effect of TRIB1 Variant on Lipid Profile and Coronary Artery Disease: A Systematic Review and Meta-Analysis

Effect of TRIB1 Variant on Lipid Profile and Coronary Artery Disease: A Systematic Review and Meta-Analysis

ATF3 and its emerging role in atherosclerosis: a narrative review

Nanobodies identify an activated state of the TRIB2 pseudokinase

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