Interdependent biological systems, multi-functional molecules: The evolving role of tissue factor pathway inhibitor beyond anti-coagulation

Holroyd, Eric W.; Simari, Robert D.

doi:10.1016/j.thromres.2010.01.039

Cited by 13 publications

(7 citation statements)

References 36 publications

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“…The lipid and haemostatic systems are closely intertwined, mediating the pathological processes of inflammation and thrombosis (67). TFPI is transported by low-density lipoprotein cholesterol, and plasma levels of TFPI correlate with measures of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and markers of endothelial cell dysfunction, a hallmark of inflammation (4,10,68).…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of tissue factor pathway inhibitor plasma levels

Dennis¹,

Kassam²,

Morange³

et al. 2015

Thromb Haemost

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Tissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene.

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Section: Discussionmentioning

confidence: 99%

Genetic determinants of tissue factor pathway inhibitor plasma levels

Dennis¹,

Kassam²,

Morange³

et al. 2015

Thromb Haemost

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“…Thus, TFPI plays a protective role in maintaining cellular and systemic homeostasis of immune system. Additionally, TFPI has been demonstrated to be involved in three interdependent biological processes that is coagulation, angiogenesis and lipid metabolism (Holroyd and Simari, 2010). Excess cellular lipid forms lipotoxic metabolites (such as cholesterol crystals) which on one hand induce inflammatory cytokine production and on the other induce TFPI (Holroyd and Simari, 2010; Espada et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, TFPI has been demonstrated to be involved in three interdependent biological processes that is coagulation, angiogenesis and lipid metabolism (Holroyd and Simari, 2010). Excess cellular lipid forms lipotoxic metabolites (such as cholesterol crystals) which on one hand induce inflammatory cytokine production and on the other induce TFPI (Holroyd and Simari, 2010; Espada et al, 2017). TFPI not only regulates the inflammatory processes through their inhibition but also reduces cholesterol concentration (through stimulation of internalization and degradation of VLDLs through HSPG-dependent pathway) (Holroyd and Simari, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Excess cellular lipid forms lipotoxic metabolites (such as cholesterol crystals) which on one hand induce inflammatory cytokine production and on the other induce TFPI (Holroyd and Simari, 2010; Espada et al, 2017). TFPI not only regulates the inflammatory processes through their inhibition but also reduces cholesterol concentration (through stimulation of internalization and degradation of VLDLs through HSPG-dependent pathway) (Holroyd and Simari, 2010). ANGPTL8 has also been previously demonstrated as an integral component of lipid metabolism.…”

Section: Resultsmentioning

confidence: 99%

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Biological Pathways Leading From ANGPTL8 to Diabetes Mellitus–A Co-expression Network Based Analysis

et al. 2018

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Angiopoietin like protein 8 (ANGPTL8) is a newly identified hormone with unique nature due to its ability to regulate both glucose and lipid metabolic pathways. It is characterized as an important molecular player of insulin induced nutrient storage and utilization pathway during fasting to re-feeding metabolic transition. Several studies have contributed to increase our knowledge regarding its function and mechanism of action. Moreover, its altered expression levels have been observed in Insulin Resistance, Diabetes Mellitus (Types I & II) and Non Alcohlic Fatty Liver Disease emphasizing its assessment as a drug target. However, there is still a great deal of information that remains to be investigated including its associated biological processes, partner proteins in these processes, its regulators and its association with metabolic pathogenesis. In the current study, the analysis of a transcriptomic data set was performed for functional assessment of ANGPTL8 in liver. Weighted Gene Co-expression Network Analysis coupled with pathway analysis tools was performed to identify genes that are significantly co-expressed with ANGPTL8 in liver and investigate their presence in biological pathways. Gene ontology term enrichment analysis was performed to select the gene ontology classes that over-represent the hepatic ANGPTL8-co-expressed genes. Moreover, the presence of diabetes linked SNPs within the genes set co-expressed with ANGPTL8 was investigated. The co-expressed genes of ANGPTL8 identified in this study (n = 460) provides narrowed down list of molecular targets which are either co-regulated with it and/or might be regulation partners at different levels of interaction. These results are coherent with previously demonstrated roles and regulators of ANGPTL8. Specifically, thirteen co-expressed genes (MAPK8, CYP3A4, PIK3R2, PIK3R4,PRKAB2, G6PC, MAP3K11, FLOT1, PIK3C2G, SHC1, SLC16A2, and RAPGEF1) are also present in the literature curated pathway of ANGPTL8 (WP39151). Moreover, the gene-SNP analysis of highly associated biological processes with ANGPTL8 revealed significant genetic signals associated to Diabetes Mellitus and similar phenotypic traits. It provides meaningful insights on the influencing genes involved and co-expressed in these pathways. Findings of this study have implications in functional characterization of ANGPTL8 with emphasis on the identified genes and pathways and their possible involvement in the pathogenesis of Diabetes Mellitus and Insulin Resistance.

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“…41 Moreover, TFPI on endothelial and other cells probably has roles beyond the control of TF procoagulant activity, 30 such as modulation of innate immunity, angiogenesis, and lipid metabolism. 42 It will be interesting to elucidate whether APC affects these functions of TFPI.…”

Section: Discussionmentioning

confidence: 99%