ABSTRACT
OBJECTIVE: Resistin-like molecule (RELM) ß is a secretory protein homologous to resistin and reportedly contributes to local immune response regulation in gut and bronchial epithelial cells. However, we found that activated macrophages also express RELMß and thus investigated the role of RELMß in the development of atherosclerosis. APPROACH AND RESULTS: It was demonstrated that foam cells in atherosclerotic lesions of the human coronary artery abundantly express RELMß. RELMß knockout ((-/-)) and wild-type mice were mated with apolipoprotein E-deficient background mice. RELMß(-/-) apolipoprotein E-deficient mice exhibited less lipid accumulation in the aortic root and wall than RELMß(+/+) apolipoprotein E-deficient mice, without significant changes in serum lipid parameters. In vitro, RELMß(-/-) primary cultured peritoneal macrophages (PCPMs) exhibited weaker lipopolysaccharide-induced nuclear factor-κB classical pathway activation and inflammatory cytokine secretion than RELMß(+/+), whereas stimulation with RELMß upregulated inflammatory cytokine expressions and increased expressions of many lipid transporters and scavenger receptors in PCPMs. Flow cytometric analysis revealed inflammatory stimulation-induced RELMß in F4/80(+) CD11c(+) PCPMs. In contrast, the expressions of CD11c and tumor necrosis factor were lower in RELMß(-/-) PCPMs, but both were restored by stimulation with recombinant RELMß. CONCLUSIONS: RELMß is abundantly expressed in foam cells within plaques and contributes to atherosclerosis development via lipid accumulation and inflammatory facilitation.
Subject(s)
Atherosclerosis/metabolism , Foam Cells/metabolism , Hormones, Ectopic/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Aorta/immunology , Aorta/metabolism , Aorta/pathology , Apolipoproteins E/genetics , Atherosclerosis/immunology , Atherosclerosis/pathology , CD11c Antigen/metabolism , Cell Line , Fatty Acids/pharmacology , Female , Foam Cells/immunology , Foam Cells/pathology , Hormones, Ectopic/genetics , Hormones, Ectopic/immunology , Humans , Intercellular Signaling Peptides and Proteins/immunology , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/pathology , Male , Mice , Mice, Knockout , Primary Cell Culture , Vasculitis/immunology , Vasculitis/metabolism , Vasculitis/pathologyABSTRACT
The differentiation of macrophages into cytokine-secreting foam cells plays a critical role in the development of diabetic angiopathy. J774.1, a murine macrophage cell line, reportedly differentiates into foam cells when incubated with oxidized LDL, ApoE-rich VLDL or WHHLMI (myocardial infarction-prone Watanabe heritable hyperlipidemic) rabbit serum. In this study, serum samples from Type 2 diabetic patients were added to the medium with J774.1 cells and the degree of foam cell induction was quantified by measuring lipid accumulation. These values were calculated relative to the activities of normal and WHHLMI rabbit sera as 0% and 100%, respectively, and termed the MMI (Macrophage Maturation Index). These MMI values reflected intracellular lipids, including cholesteryl ester assayed by GC/MS. Statistical analysis revealed MMI to correlate positively and independently with serum triglycerides, the state of diabetic retinopathy, nephropathy and obesity, but negatively with administration of alpha-glucosidase inhibitors or thiazolidinediones. Taken together, our results suggest that this novel assay may be applicable to the identification of patients at risk for rapidly progressive angiopathic disorders.
Subject(s)
Diabetic Angiopathies/blood , Foam Cells/physiology , Macrophages/physiology , Animals , Blood Pressure , Body Mass Index , Cell Culture Techniques , Cell Differentiation , Female , Glycated Hemoglobin/analysis , Humans , Leukocyte Count , Lipids/blood , Lipids/isolation & purification , Lipoproteins, HDL/blood , Lipoproteins, LDL/pharmacology , Liver Function Tests , Macrophages/cytology , Macrophages/drug effects , Male , Mice , Rabbits , Regression AnalysisABSTRACT
AIMS: Energy sensing systems including AMPK and SIRT1 play important roles in the regulation of hepatic gluconeogenesis and fatty acid oxidation. In this study, we investigated how hepatic LKB1-AMPK signaling and SIRT1 expression are altered after 2 or 8 weeks of HFD feeding. METHODS: The livers of male mice fed a HFD or a standard diet for 2 or 8 weeks were removed. The expression and phosphorylation levels of LKB1, AMPK, ACC and TORC2, and SIRT1 expression levels were examined by immunoblotting. RESULTS: In mice fed a HFD for 2 weeks, the phosphorylations of AMPKα and ACC were decreased without significant alterations in LKB1 phosphorylation or SIRT1 protein levels, while TORC2 protein levels were increased. In mice fed a HFD for 8 weeks, marked reductions in LKB1 phosphorylation and SIRT1 protein amount were observed in addition to the decreased phosphorylations of AMPKα and ACC. CONCLUSIONS: The mechanisms underlying impaired energy sensing signaling differ with the duration of HFD feeding. In the early phase of HFD feeding, LKB1 and SIRT1 were not impaired, while in the later phase of HFD feeding, decreased SIRT1 expression and LKB1 phosphorylation may be involved in the development of severe glucose and lipid intolerance.
