TY  - JOUR
A1  - Fayyaz, Susann
A1  - Japtok, Lukasz
A1  - Schumacher, Fabian
A1  - Wigger, Dominik
A1  - Schulz, Tim Julius
A1  - Haubold, Kathrin
A1  - Gulbins, Erich
A1  - Völler, Heinz
A1  - Kleuser, Burkhard
T1  - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - 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.
KW  - Lysophosphatidic acid
KW  - Insulin signaling
KW  - Adipose tissue
KW  - Autotaxin
KW  - Hepatic insulin resistance
KW  - LPA(3) receptor subtype
Y1  - 2017
U6  - https://doi.org/10.1159/000480470
SN  - 1015-8987
SN  - 1421-9778
VL  - 43
SP  - 445
EP  - 456
PB  - Karger
CY  - Basel
ER  -