TY - JOUR
AU - Lebeche, Djamel
AB - This commentary refers to ‘Metabolism reprogramming: new insights of Dlk1 into cardiac fibrosis’, by X.-Q. Yang et al., 2019:40:3574. We thank Dr Da-Xin Wang et al. for their valuable comments regarding our publication highlighting the role of Dlk1 in regulating myocardial fibrotic response.1 The suggestion that other secreted bioactive factors in Dlk1-null mice (i.e. ostepontin and leptin, and probably others) might be involved in cardiac fibrogenesis is very likely and worth-exploring. Multiple recent publications have documented ostepontin as a non-invasive biomarker of cardiovascular events and hepatic fibrosis in patients2 and is associated with liver and lung fibrosis. However, given the documented anti-adipogenic function of Dlk1, it is strongly believed that Dlk1 would have a direct effect on circulating fatty acids (FA) and subsequent lipotoxicity-induced cardiac remodelling. Intramyocardial accumulation of FA leads to cardiac damage in part via accumulation of free radicals, apoptosis, and consequent changes in gene expression associated with contractile impairment. Recently, miR-370, a target of Dlk1 regulation, has been reported to negatively modulate the expression of perilipin 5 in cardiomyocytes leading to suppression of apoptosis following myocardial ischaemia/reperfusion injury.3 Perilipin 5 is a lipid-droplet-associated protein involved in FA catabolism and mitochondrial oxidation. This finding lends support for a role for Dlk1 in controlling cardiac remodelling through the activation of miR-370 leading to inhibition of TGF-β1/Smad3 signalling pathway or attenuation of perilipin 5-associated lipid accumulation. The suggestion that elevated levels of Dlk1 are detrimental must be taken with caution as there are multiple cases where up-regulation of Dlk1 is needed and is beneficial. For example, besides cardiac fibrosis, low levels of Dlk1 were associated with pregnancy complications such as hyperglycaemia, neonatal morbidity, and abnormalities in blood flow in the umbilical artery and circumference growth velocity.4 Increased Dlk1 expression has been reported to regulate gluconeogenesis and protect against liver steatosis,5 and to promote pancreatic ductal and beta-cell regeneration after injury leading to improved glucose homoeostasis. Furthermore, Dlk1 expression is important in promoting lung alveolar repair and neurogenesis6 or inhibiting angiogenesis. Given the diverse, often controversial, functions of Dlk1, we, therefore, would like to emphasize that the actions of Dlk1 must be interpreted keeping in mind the following considerations: (i) isoform specificity, i.e. distinct roles of membrane vs. soluble Dlk1; for example, soluble Dlk1 inhibits adipocyte differentiation, whereas membrane-bound Dlk1 regulates neural stem cell number6; (ii) tissue/organ-level context; (iii) disease specificity; (iv) Dlk1 expression dosage; and (v) time/age-dependence, i.e. neonatal vs. adult stages. These considerations are functionally important in fully understanding the biological actions of Dlk1. Conflict of interest: none declared. References 1 Yang X-Q , Zhao F-F , Wang D-X . Metabolism reprogramming: new insights of Dlk1 into cardiac fibrosis . Eur Heart J 2019 ; 40 : 3574 . WorldCat 2 Pereira TA , Syn WK , Pereira FE , Lambertucci JR , Secor WE , Diehl AM. Serum osteopontin is a biomarker of severe fibrosis and portal hypertension in human and murine schistosomiasis mansoni . Int J Parasitol 2016 ; 46 : 829 – 832 . Google Scholar Crossref Search ADS WorldCat 3 Zhao YB , Zhao J , Zhang LJ , Shan RG , Sun ZZ , Wang K , Chen JQ , Mu JX. MicroRNA-370 protects against myocardial ischemia/reperfusion injury in mice following sevoflurane anesthetic preconditioning through PLIN5-dependent PPAR signaling pathway . Biomed Pharmacother 2019 ; 113 : 108697 . Google Scholar Crossref Search ADS WorldCat 4 Cleaton MA , Dent CL , Howard M , Corish JA , Gutteridge I , Sovio U , Gaccioli F , Takahashi N , Bauer SR , Charnock-Jones DS , Powell TL , Smith GC , Ferguson-Smith AC , Charalambous M. Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction . Nat Genet 2016 ; 48 : 1473 – 1480 . Google Scholar Crossref Search ADS WorldCat 5 Charalambous M , Da Rocha ST , Radford EJ , Medina-Gomez G , Curran S , Pinnock SB , Ferrón SR , Vidal-Puig A , Ferguson-Smith AC. DLK1/PREF1 regulates nutrient metabolism and protects from steatosis . Proc Natl Acad Sci U S A 2014 ; 111 : 16088 – 16093 . Google Scholar Crossref Search ADS WorldCat 6 Ferrón SR , Charalambous M , Radford E , McEwen K , Wildner H , Hind E , Morante-Redolat JM , Laborda J , Guillemot F , Bauer SR , Fariñas I , Ferguson-Smith AC. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis . Nature 2011 ; 475 : 381 – 385 . Google Scholar Crossref Search ADS WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Response to ‘Metabolism reprogramming: new insights of Dlk1 into cardiac fibrosis’
JO - European Heart Journal
DO - 10.1093/eurheartj/ehz604
DA - 2019-09-05
UR - https://www.deepdyve.com/lp/oxford-university-press/response-to-metabolism-reprogramming-new-insights-of-dlk1-into-cardiac-H3JpHVbv8S
SP - 3575
EP - 3575
VL - 40
IS - 43
DP - DeepDyve
ER -