Lysophosphatidylcholine activates adipocyte glucose uptake and lowers blood glucose levels in murine models of diabetes.
ABSTRACT Glucose homeostasis is maintained by the orchestration of peripheral glucose utilization and hepatic glucose production, mainly by insulin. In this study, we found by utilizing a combined parallel chromatography mass profiling approach that lysophosphatidylcholine (LPC) regulates glucose levels. LPC was found to stimulate glucose uptake in 3T3-L1 adipocytes dose- and time-dependently, and this activity was found to be sensitive to variations in acyl chain lengths and to polar head group types in LPC. Treatment with LPC resulted in a significant increase in the level of GLUT4 at the plasma membranes of 3T3-L1 adipocytes. Moreover, LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with the PI 3-kinase inhibitor LY294002. However, glucose uptake stimulation by LPC was abrogated both by rottlerin (a protein kinase Cdelta inhibitor) and by the adenoviral expression of dominant negative protein kinase Cdelta. In line with its determined cellular functions, LPC was found to lower blood glucose levels in normal mice. Furthermore, LPC improved blood glucose levels in mouse models of type 1 and 2 diabetes. These results suggest that an understanding of the mode of action of LPC may provide a new perspective of glucose homeostasis.
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ABSTRACT: Preclinical ResearchOxidized low-density lipoprotein (ox-LDL) is implicated in many inflammatory diseases, e.g., type 2 diabetes, obesity, atherosclerosis, and metabolic syndrome. We previously reported that a synthetic biotinylated peptide, BP21, inhibits the bioactivity of ox-LDL via direct binding to ox-LDL. Here, we investigated the effect of BP21 on the mRNA expression of proinflammatory mediators induced by two major components of ox-LDL, oxidized- and lyso-phosphatidylcholine (ox-PC and LPC), in monocytes/macrophages (THP-1 cells) and adipocytes (3T3-L1 cells). In THP-1 cells, BP21 markedly reduced the mRNA expression of interleukin (IL)-6, adipocyte fatty acid-binding protein (aP2), tumor necrosis factor-α, and mitogen-activated protein kinase phosphatase-1, which are induced by one of the major bioactive components of ox-PC, 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), and reduced the mRNA expression of IL-6, the ox-LDL-specific scavenger receptor CD36, and aP2 induced by LPC. In adipocytes, the mRNA expression of IL-1β as an adipokine and aP2 is highly induced by ox-PC and LPC, and BP21 markedly reduced the mRNA expression of IL-1β and aP2 induced by POVPC and LPC. Furthermore, BP21 specifically bound to LPC and POVPC in a dose-dependent manner. These results suggest that BP21 may be useful lead for the potential treatment and prevention of inflammatory diseases caused by ox-PC and LPC.Drug Development Research 06/2014; · 0.87 Impact Factor
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ABSTRACT: Gestational Diabetes (GDM) is causing severe short- and long-term complications for mother, fetus or neonate. As yet, the metabolic alterations that are specific for the development of GDM have not been fully determined, which also precludes the early diagnosis and prognosis of this pathology. In this pilot study, we determine the metabolic fingerprint, using a multiplatform LC-QTOF/MS, GC-Q/MS and CE-TOF/MS system, of plasma and urine samples of 20 women with GDM and 20 with normal glucose tolerance in the second trimester of pregnancy. Plasma fingerprints allowed for the discrimination of GDM pregnant women from controls. In particular, lysoglycerophospholipids showed a close association with the glycemic state of the women. In addition, we identified some metabolites with a strong discriminative power, such as LPE(20:1), (20:2), (22:4); LPC(18:2), (20:4), (20:5); LPI(18:2), (20:4); LPS(20:0) and LPA(18:2), as well as taurine-bile acids and long-chain polyunsaturated fatty acids derivatives. Finally, we provide evidence for the implication of these compounds in metabolic routes, indicative of low-grade inflammation and altered redox-balance, that may be related with the specific pathophysiological context of the genesis of GDM. This highlights their potential use as prognostic markers for the identification of women at risk to develop severe glucose intolerance during pregnancy. Gestational Diabetes Mellitus (GDM) is increasing worldwide and, although diabetes usually remits after pregnancy, women with GDM have a high risk of developing postpartum type 2-diabetes, particularly when accompanied by obesity. Therefore, understanding the pathophysiology of GDM, as well as the identification of potentially modifiable risk factors and early diagnostic markers for GDM are relevant issues. In the present study, we devised a multiplatform metabolic fingerprinting approach to obtain a comprehensive picture of the early metabolic alternations that occur in GDM, and may reflect on the specific pathophysiological context of the disease. Future studies at later stages of gestation will allow us to validate the discriminant power of the identified metabolites.Journal of proteomics 03/2014; · 5.07 Impact Factor
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ABSTRACT: The objectives of the present study were to (1) examine the effects of the phenotypic factors age, gender and BMI on the lipidomic profile and (2) investigate the relationship between the lipidome, inflammatory markers and insulin resistance. Specific ceramide, phosphatidylcholine and phosphatidylethanolamine lipids were increased in females relative to males and specific lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine and phosphatidylethanolamine lipids decreased as BMI increased. However, age had a minimal effect on the lipid profile with significant differences found in only two lipid species. Network analysis revealed strong negative correlations between the inflammatory markers CRP, TNF-α, resistin and MCP-1 and lipids in the LPC, PC and PE classes, whereas IL-8 formed positive correlations with lipids from the CER and SM classes. Further analysis revealed that LPC a C18:1 and PE ae C40:6 were highly associated with insulin resistance as indicated by HOMA-IR score. The present study identified lipids that are affected by BMI and gender and identified a series of lipids which had significant relationships with inflammatory markers. LPC a C18:1 and PE ae C40:6 were found to be highly associated with insulin resistance pointing to the possibility that the alterations in these specific lipids may play a role in the development of insulin resistance.Molecular BioSystems 04/2014; · 3.35 Impact Factor