Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

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 (LPA_1-6). 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.

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

“…Two very recent studies have provided more direct evidence for an inhibitory role of ATX-LPA signaling on tissue insulin function (21,44). Acute pretreatment of primary rat hepatocytes with LPA decreased insulin-stimulated AKT phosphorylation, glucokinase, and SREBP-1c expression, PI3K activation, and glycogen synthesis, likely via LPA1 and/or LPA3 (44). Moreover, inhibition of ATX protected against interleukin 6-induced impairment of insulin-stimulated AKT phosphorylation in 3T3-L1 adipocytes (21).…”

“…Only a few prior studies have examined the effect of ATX-LPA signaling on tissue insulin function (21,24,44). Rancoule et al (24) showed that administration of a LPA1/3 receptor antagonist in high-fat diet-fed mice for 3 weeks improves insulin sensitivity and increases insulinstimulated glucose oxidation in muscle ex vivo, suggesting that LPA signaling through LPA1/3 impairs muscle insulin function.…”

“…However, other effects of systemic LPA1/3 inhibition, including increased pancreatic islet mass and liver glycogen storage, may have contributed to changes in glucose metabolism in muscle (24). Two very recent studies have provided more direct evidence for an inhibitory role of ATX-LPA signaling on tissue insulin function (21,44). Acute pretreatment of primary rat hepatocytes with LPA decreased insulin-stimulated AKT phosphorylation, glucokinase, and SREBP-1c expression, PI3K activation, and glycogen synthesis, likely via LPA1 and/or LPA3 (44).…”

Skeletal Muscle Tissue Trib3 Links Obesity with Insulin Resistance by Autophagic Degradation of AKT2

“…Although both environmental factors and genetic susceptibility contribute to insulin sensitivity and resistance, the regulation of AKT activity may play a pivotal role in insulin-mediated signal transduction because mice lacking Akt develop diabetes due to their resistance to insulin signaling [1][2][3].…”

Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation

“…LPA is able to attenuate insulin signaling in rat hepatocytes via LPA 3 signaling through decreased hepatocyte glucose uptake and glycogen synthesis [ 91 ]. In the same study, the authors reported LPA 16:0 concentrations to be about 25 percent higher in obese patients with a body mass index (BMI) >30 compared to normal weight individuals (BMI 18.5–25) [ 91 ].…”