ArticlePloS one2015
Modulators of hepatic lipoprotein metabolism identified in a search for small-molecule inducers of tribbles pseudokinase 1 expression.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.Circulation research · 2026Review
- Mechanisms of action and therapeutic potential of PCSK9-regulating drugs.Pharmaceutical biology · 2025Review
- Gene editing therapy for cardiovascular diseases.MedComm · 2024Review
- Review
- Pre-Diabetes-Linked miRNA miR-193b-3p Targets PPARGC1A, Disrupts Metabolic Gene Expression Profile and Increases Lipid Accumulation in Hepatocytes: Relevance for MAFLD.International journal of molecular sciences · 2023Article
- The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases.Frontiers in genetics · 2022Review
- Current Progress in Delineating the Roles of Pseudokinase TRIB1 in Controlling Human Diseases.Journal of Cancer · 2021Review
- Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects.Signal transduction and targeted therapy · 2020Review
- Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice.Scientific reports · 2019Article
- Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators.Bioorganic & medicinal chemistry letters · 2019Article
- Novel tricyclic glycal-basedMedChemComm · 2018Article
- Chemical probes and drug leads from advances in synthetic planning and methodology.Nature reviews. Drug discovery · 2018Review
- A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia.Cell stem cell · 2017Article
- The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol.Global cardiology science & practice · 2017Review
- Genome editing in cardiovascular diseases.Nature reviews. Cardiology · 2017Review
- Genetics and Genomics of Coronary Artery Disease.Current cardiology reports · 2016Review
- Advances in discovering small molecules to probe protein function in a systems context.Current opinion in chemical biology · 2016Review
- Tribbles-1: a novel regulator of hepatic lipid metabolism in humans.Biochemical Society transactions · 2015Review
- Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα.The Journal of clinical investigation · 2015Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.