Susann Fayyaz1, Lukasz Japtok1, Fabian Schumacher1,2, Dominik Wigger1, Tim Julius Schulz3, Kathrin Haubold4, Erich Gulbins2, Heinz Völler4,5, Burkhard Kleuser1,6. 1. Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Potsdam, Germany. 2. Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany. 3. German Institute of Human Nutrition (DIfE), Department of Adipocyte Development and Nutrition, Potsdam-Nuthetal, Germany. 4. Centre of Rehabilitation Research, Human Sciences Faculty, University of Potsdam, Potsdam, Germany. 5. Klinik am See, Rehabilitation Centre for Internal Medicine, Rüdersdorf, Germany. 6. Nutriact - Competence Cluster Nutrition Research Berlin-Potsdam, Potsdam, Germany.
Abstract
BACKGROUND/AIMS: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). METHODS: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). RESULTS: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). CONCLUSION: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
BACKGROUND/AIMS: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). METHODS: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). RESULTS: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obeseparticipants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). CONCLUSION:LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipidLPA (16: 0) is increased in obesity.
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