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Thromb Haemost 2016; 116(02): 379-393
DOI: 10.1160/TH15-10-0773
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin β-Receptor pathway

Irene Andrés-Blasco
1   Institute of Health Research-INCLIVA, Valencia, Spain
,
Àngela Vinué
1   Institute of Health Research-INCLIVA, Valencia, Spain
,
Andrea Herrero-Cervera
1   Institute of Health Research-INCLIVA, Valencia, Spain
,
Sergio Martínez-Hervás
1   Institute of Health Research-INCLIVA, Valencia, Spain
2   Endocrinology and Nutrition Department Clinic Hospital and Department of Medicine, University of Valencia, Spain
3   CIBERDEM, Madrid, Spain
,
Laura Nuñez
1   Institute of Health Research-INCLIVA, Valencia, Spain
,
Laura Piqueras
1   Institute of Health Research-INCLIVA, Valencia, Spain
,
Juan F. Ascaso
1   Institute of Health Research-INCLIVA, Valencia, Spain
2   Endocrinology and Nutrition Department Clinic Hospital and Department of Medicine, University of Valencia, Spain
3   CIBERDEM, Madrid, Spain
,
MarÍa Jesús Sanz
1   Institute of Health Research-INCLIVA, Valencia, Spain
4   Department of Farmacology, University of Valencia, Spain
,
Deborah Jane Burks
3   CIBERDEM, Madrid, Spain
5   Centro de Investigacion Principe Felipe, Valencia, Spain
,
Herminia González-Navarro
1   Institute of Health Research-INCLIVA, Valencia, Spain
3   CIBERDEM, Madrid, Spain
› Author Affiliations Financial support: This study was supported by grants from the Carlos III Health Institute (CP10/00555 and PI13/00834 to HG-N) from the Spanish Ministry of Economy and Competitiveness (SAF2011–23777 to MJS), from the European Regional Development Fund (FEDER) and Generalitat Valenciana (GVACOMP2014–006 and PROMETEO II/2013/014 to MJS). H. G.-N. is a ‘Miguel Servet’ investigator (CP10/00555). I.A-B. and A. V. received salary support from Proyecto Paula. This work was supported by CIBERDEM.
Further Information

Publication History

Received: 05 October 2015

Accepted after major revision: 24 April 2016

Publication Date:
09 March 2018 (online)

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Summary

Coexistence of insulin resistance (IR) and metabolic syndrome (MetS) increases the risk of cardiovascular disease (CVD). Genetic studies in diabetes have linked Hepatic Lipase (HL) to an enhanced risk of CVD while others indicate a role of HL in inflammatory cells. Thus, we explored the role of HL on atherosclerosis and inflammation in a mouse model of MetS/IR, (apoE-/-Irs2+/- mice) and in patients with MetS and IR. HL-deficiency in apoE-/-Irs2+/- mice reduced atheroma size, plaque vulnerability, leukocyte infiltration and macrophage proliferation. Compared with apoE-/-Irs2+/-HL+/+ mice, MCP1, TNFa and IL6 plasma levels, pro-inflammatory Ly6Chi monocytes and activated(CD69+)-T lymphocytes were also decreased in apoE-/-Irs2+/-HL-/- mice. The LIGHT (Tumour necrosis factor ligand superfamily member 14, TNFSF14)/ Lymphotoxin β-Receptor(LTβ-R) pathway, which is involved in T-cell and macrophage activation, was diminished in plasma and in apoE-/-Irs2+/-HL-/- mouse atheromas. Treatment of apoE-/-Irs2+/-HL-/- mice with LIGHT increased the number of Ly6Chi-monocytes and lesion size. Acutely LIGHT-treated apoE-/- mice displayed enhanced proliferating Ly6Chi-monocytes and increased activation of the mitogen-activated protein kinase p38, suggesting that LIGHT/LTβ-R axis might promote atherogenesis by increasing proinflammatory monocytes and proliferation. Notably, MetS-IR subjects with increased atherosclerosis displayed up-regulation of the LIGHT/LTβ-R axis, enhanced inflammatory monocytes and augmented HL mRNA expression in circulating leukocytes. Thus, HL-deficiency decreases atherosclerosis in MetS/IR states by reducing inflammation and macrophage proliferation which are partly attributed to reduced LIGHT/LTβ-R pathway. These studies identify the LIGHT/LTβ-R axis as a main pathway in atherosclerosis and suggest that its inactivation might ameliorate inflammation and macrophage proliferation associated with atherosclerosis burden in MetS/IR.

Supplementary Material to this article is available at www.thrombosis-online.com.

Keywords

Atherosclerosis - inflammation - insulin resistance - hepatic lipase - macrophage

 

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