title: Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin β-Receptor pathway.
abstract: 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, TNFα 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.
authors.forename: Irene
authors.initials: I
authors.lastname: Andrés-Blasco
authors.forename: Ángela
authors.initials: Á
authors.lastname: Vinué
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrero-Cervera
authors.forename: Sergio
authors.initials: S
authors.lastname: Martínez-Hervás
authors.forename: Laura
authors.initials: L
authors.lastname: Nuñez
authors.forename: Laura
authors.initials: L
authors.lastname: Piqueras
authors.forename: Juan F
authors.initials: JF
authors.lastname: Ascaso
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Deborah Jane
authors.initials: DJ
authors.lastname: Burks
authors.affiliation: Herminia González-Navarro, Institute of Health Research-INCLIVA, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain, Tel.: +34 96 386 44 03, Fax: +34 96 398 78 60, E-mail: gonzaleh@uv.es.
authors.forename: Herminia
authors.initials: H
authors.lastname: González-Navarro
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D008049:Lipase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074085:Mice, Knockout, ApoE; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D012333:RNA, Messenger; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D048051:p38 Mitogen-Activated Protein Kinases; D008049:Lipase; C495700:Lipc protein, mouse
keywords: Atherosclerosis; hepatic lipase; inflammation; insulin resistance; macrophage