Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study

Hess, Anne Lundby; Carayol, Jérôme; Blædel, Trine; Hager, Jörg; Cara, Alessandro Di; Astrup, Arne; Larsen, Lesli H.; Valsesia, Armand

doi:10.1186/s12263-018-0597-3

Cited by 16 publications

(10 citation statements)

References 54 publications

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“… 17 All animal experiments were approved by the Institutional Animal Care and Use Committee of the National University of Singapore and performed in accordance with Singapore National Advisory Committee for Laboratory Animal Research guidelines. 18 …”

Section: Methodsmentioning

confidence: 99%

Prioritizing Candidates of Post–Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics

et al. 2020

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Background: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. Methods: We employed aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at one month post-MI in a New Zealand cohort (CDCS) including 181 post-MI patients who were subsequently hospitalized for HF compared with 250 post-MI patients who remained event-free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially co-regulated in post-MI HF using Weighted Gene Co-expression Network Analysis (WCGNA). A Singapore cohort (IMMACULATE) of 223 post-MI patients, of which 33 patients were hospitalized for HF (median follow-up 2.0 years), was used for further candidate enrichment of plasma proteins using Fisher meta-analysis, resampling-based statistical testing and machine learning. We then cross-referenced differentially-expressed proteins with their differentially-expressed genes from single-cell transcriptomes of non-myocyte cardiac cells isolated from a murine MI model, and single-cell and single-nuclei transcriptomes of cardiac myocytes from murine HF models and human HF patients. Results: In the CDCS cohort, 212 differentially-expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. WCGNA prioritised 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF compared with event-free controls (dataset 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (dataset 2) while single-cell transcriptomes identified 15 gene-protein candidates (dataset 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly-enriched proteins that were common to all 3 datasets included well-established biomarkers of post-MI HF - N-terminal B-type natriuretic peptide and troponin T - as well as newly-emergent biomarkers - angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4 and follistatin-related protein-3. Conclusions: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac cell transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.

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Section: Methodsmentioning

confidence: 99%

Prioritizing Candidates of Post–Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics

et al. 2020

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“…Therefore, we speculated that the cause of death in mice receiving ADR injection was not only cardiac dysfunction, but also abnormal liver function. Previous studies suggest Angptl3 is mainly produced by the liver [4] and associated with liver health [36]. A higher proportion of Angptl3+/+ mice than Angptl3−/− mice died throughout our observation period, which might indicate that the Angptl3 knockout also played an important role in hepatic protection.…”

Section: Discussionmentioning

confidence: 77%

Angiopoietin-like-3 knockout protects against glomerulosclerosis in murine adriamycin-induced nephropathy by attenuating podocyte loss

et al. 2019

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Background Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. The current study re-evaluated the renoprotective effect of Angptl3 knockout in chronic ADR nephropathy and attempted to explore the mechanism underlying the effect associated with Angptl3 knockout in glomerulosclerosis. Methods B6; 129S5 mice were injected with ADR to induce nephropathy. Kidney structure and serum and urine parameters were observed during long-term follow-up. Cultured primary mouse podocytes were exposed to ADR and analyzed for the expression of some relative proteins. Podocyte loss was analyzed in both in vivo and in vitro experiments. Results Angptl3 knockout attenuated proteinuria and hypoproteinemia, protected renal structure and function, and improved the survival of mice over the whole process of ADR nephropathy. Furthermore, Angptl3 knockout reduced the numbers of the detached and apoptotic cells in the renal tissue and alleviated podocyte loss in mice with ADR chronic nephropathy, thereby, delaying the glomerulosclerosis formation. Additional results in vitro showed that Angptl3 knockout attenuated ADR-induced primary podocyte loss, including podocyte detachment and apoptosis. Conclusion In addition to serving a renoprotective role in the early stage of ADR nephropathy, Angptl3 knockout contributed to disease amelioration throughout the ADR nephropathy process. Angptl3 knockout effectively delayed glomerulosclerosis formation by attenuating podocyte loss through rescuing podocytes from detachment and apoptosis. Angptl3 antagonists or inhibitors might have therapeutic potential in the occurrence and progression of nephropathy. Electronic supplementary material The online version of this article (10.1186/s12882-019-1383-1) contains supplementary material, which is available to authorized users.

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“…These results contrast with the role of ANGPTL3 in the lipid phenotype called familial combined hypolipidemia (FHBL2, OMIM #605019) 20 , in which LOF mutations in ANGPTL3 are responsible of reduced plasma levels of TC, triglycerides, VLDL cholesterol, LDLc, apoB, and free fatty acids, just the opposite lipid pro le found in FCHL. Furthermore, FCHL and familial combined hypolipidemia share abnormal hepatic VLDL secretion rates as the main mechanism of the lipid abnormalities, being increased in FCHL 37,38 and decreased in familial combined hypolipidemia 39 .…”

Section: Discussionmentioning

confidence: 99%

ANGPTL3 Gene Variants in Subjects With Familial Combined Hyperlipidemia

Bea

Franco-Marín

Marco-Benedí

et al. 2021

Preprint

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Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans. Loss-of-function variants in ANGPTL3 cause a monogenic disease named familial combined hypolipidemia. However, the potential contribution of ANGPTL3 gene in subjects with familial combined hyperlipidemia (FCHL) has not been studied. To study the gain-of-function (GOF) genetic variants in the ANGPTL3 gene in FCHL subjects and to establish the potential contribution of ANGPTL3 in the aetiology of FCHL. ANGPTL3 gene was sequenced in 162 unrelated subjects with severe FCHL and 165 normolipemic controls. Pathogenicity of genetic variants was predicted with PredictSNP2 and FruitFly. Frequency of identified variants in FCHL was compared with that of normolipemic controls and that described in the1000 Genomes Project. No GOF mutations in ANGPTL3 was present in subjects with FCHL. Four variants were identified in FCHL subjects, showing a frequency different from that observed in normolipemic controls: c.607-109T>C, c.607-47_607-46delGT, c.835+41C>A and c.*52_*60del. This last variant, c.*52_*60del, is a microRNA associated sequence in the 3’UTR of ANGPTL3, and it was present 2.7 times more frequently in normolipemic controls than in FCHL subjects. Our research shows that no GOF mutations in ANGPTL3 were found in a large group of unrelated subjects with FCHL.

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Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study

Cited by 16 publications

References 54 publications

Prioritizing Candidates of Post–Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics

Prioritizing Candidates of Post–Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics

Angiopoietin-like-3 knockout protects against glomerulosclerosis in murine adriamycin-induced nephropathy by attenuating podocyte loss

ANGPTL3 Gene Variants in Subjects With Familial Combined Hyperlipidemia

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