Novel tricyclic glycal-based<i>TRIB1</i>inducers that reprogram LDL metabolism in hepatic cells

Nagiec, M. Marek; Duvall, Jeremy R.; Skepner, Adam; Howe, Eleanor; Bastien, Jessica; Comer, Eamon; Marié, Jean-Charles; Johnston, Stephen; Negri, Joseph; Eichhorn, Michelle; Vantourout, Julien C.; Clish, Clary B.; Musunuru, Kiran; Foley, Michael A.; Perez, José R.; Palmer, Michelle

doi:10.1039/c8md00297e

Cited by 5 publications

(7 citation statements)

References 22 publications

(23 reference statements)

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“…Our studies in liver cells also confirm that inhibition of ERK signaling pathway by MEK1 specific inhibitor U0126 greatly reduces TRIB1 mRNA levels and abrogates the inducing effect of BBR. Our findings using BBR as a tool are consistent with other small molecules that induce TRIB1 mRNA expression 19,20 . It is worth noting that BBR was shown to induce TRIB1 mRNA expression alongside the TRIB1 inducers in HepG2 cells 19 .…”

Section: Discussionsupporting

confidence: 89%

“…Our findings using BBR as a tool are consistent with other small molecules that induce TRIB1 mRNA expression 19,20 . It is worth noting that BBR was shown to induce TRIB1 mRNA expression alongside the TRIB1 inducers in HepG2 cells 19 . Our study and the previous report on TRIB1 inducers both point to the importance of ERK signaling pathway in regulating TRIB1 gene transcription.…”

Section: Discussionsupporting

confidence: 89%

“…It was recently reported that some novel compounds termed as TRIB1 inducers were discovered through a compound library screening, these TRIB1 inducers upregulate TRIB1 mRNA levels in HepG2 cells by an ERK dependent mechanism 18,19 . To determine the involvement of ERK signaling pathway in BBR-mediated TRIB1 induction, first, we treated HepG2 cells with BBR in different time points and conducted Western blot analysis to detect activated and phosphorylated ERK (p-ERK).…”

Section: Resultsmentioning

confidence: 99%

“…Since the discovery of TRIB1 locus as a novel locus having a strong association with human plasma and hepatic lipid metabolism by several GWAS reports 5–7 , TRIB1 has been considered as a therapeutic target for developing new approaches to treat cardiometabolic diseases 19,20 . In this study, we report that the hepatic transcription of Trib1 is induced by the natural cholesterol lowering compound BBR in three different mouse models and Trib1 induction correlated strongly with plasma TG reduction regardless of the LDLR expression status.…”

Section: Discussionmentioning

confidence: 99%

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Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Singh

2019

Sci Rep

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TRIB1 is a GWAS locus associated with plasma cholesterol and triglycerides (TG) levels. In mice, liver-specific overexpression of TRIB1 lowers plasma lipid levels. Berberine (BBR) is a natural lipid lowering drug that reduces plasma LDL-cholesterol (LDL-C), total cholesterol (TC) and TG in hyperlipidemic patients and in mice by mechanisms involving upregulation of hepatic LDL receptor (LDLR). Here, we demonstrated that BBR treatment reduced plasma LDL-C, TC and TG in LDLR wildtype (WT) mice fed a high fat and high cholesterol diet and it only lowered TG in LDLR WT mice fed a normal chow diet. In hypercholesterolemic LDLR deficient mice (Ldlr−/−), BBR treatment reduced plasma TG levels by 51% compared to the vehicle control without affecting plasma cholesterol levels. Hepatic gene expression analysis revealed that Trib1 mRNA levels were significantly elevated by BBR treatment in all three mouse models and increases of Trib1 mRNA expression were associated with reduced expression of lipogenic genes including Cebpa, Acc1 and Scd1. In vitro studies further demonstrate that BBR induces TRIB1 mRNA expression by a transcriptional mechanism via ERK signaling pathway. These new findings warrant future in vivo studies to determine the causal role of Trib1 in BBR-mediated TG lowering independent of LDLR regulation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Singh

2019

Sci Rep

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“… 61 , 409 Nagiec et al identified a series of novel PCSK9 antagonists such as BRD8518 (half-maximal effective concentration [EC50] = 0.23 μM) by screening the diversity-oriented synthesis (DOS)-derived small-molecule library for compounds that upregulated expression of lipid metabolic gene TRIB1 . 410 …”

Section: Pcsk9 As a Potential Target For Multiple Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

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Discovery of 2,3′-diindolylmethanes as a novel class of PCSK9 modulators

Winston‐McPherson

Xie

Yang

et al. 2019

Bioorganic & Medicinal Chemistry Letters

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Novel tricyclic glycal-basedTRIB1inducers that reprogram LDL metabolism in hepatic cells

Abstract: Increased expression of the Tribbles pseudokinase 1 gene (TRIB1) is associated with lower plasma levels of LDL cholesterol and triglycerides, higher levels of HDL cholesterol and decreased risk of coronary artery disease.

Cited by 5 publications

References 22 publications

Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Discovery of 2,3′-diindolylmethanes as a novel class of PCSK9 modulators

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