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LXR is a negative regulator of glucose uptake in human adipocytes

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Abstract

Aims/hypothesis

Obesity increases the risk of developing type 2 diabetes mellitus, characterised by impaired insulin-mediated glucose uptake in peripheral tissues. Liver X receptor (LXR) is a positive regulator of adipocyte glucose transport in murine models and a possible target for diabetes treatment. However, the levels of LXRα are increased in obese adipose tissue in humans. We aimed to investigate the transcriptome of LXR and the role of LXR in the regulation of glucose uptake in primary human adipocytes.

Methods

The insulin responsiveness of human adipocytes differentiated in vitro was characterised, adipocytes were treated with the LXR agonist GW3965 and global transcriptome profiling was determined by microarray, followed by quantitative RT-PCR (qRT-PCR), western blot and ELISA. Basal and insulin-stimulated glucose uptake was measured and the effect on plasma membrane translocation of glucose transporter 4 (GLUT4) was assayed.

Results

LXR activation resulted in transcriptional suppression of several insulin signalling genes, such as AKT2, SORBS1 and CAV1, but caused only minor changes (<15%) in microRNA expression. Activation of LXR impaired the plasma membrane translocation of GLUT4, but not the expression of its gene, SLC2A4. LXR activation also diminished insulin-stimulated glucose transport and lipogenesis in adipocytes obtained from overweight individuals. Furthermore, AKT2 expression was reduced in obese adipose tissue, and AKT2 and SORBS1 expression was inversely correlated with BMI and HOMA index.

Conclusions/interpretation

In contrast to murine models, LXR downregulates insulin-stimulated glucose uptake in human adipocytes from overweight individuals. This could be due to suppression of Akt2, c-Cbl-associated protein and caveolin-1. These findings challenge the idea of LXR as a drug target in the treatment of diabetes.

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Abbreviations

22-R-HC:

22-R-Hydroxycholesterol

CAP:

c-Cbl associated protein

CAV1:

Caveolin 1

FAS:

Fatty acid synthase

GLUT4:

Glucose transporter 4

hMSC:

Human mesenchymal stem cell

HOMA-IR:

HOMA of insulin resistance

LXR:

Liver X receptor

miRNA:

MicroRNA

PM:

Plasma membrane

qRT-PCR:

Quantitative real-time RT-PCR

RXR:

Retinoic X receptor

SAM:

Significance analysis of microarray

SGBS:

Simpson–Golabi–Behmel syndrome

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Acknowledgements

The excellent technical assistance of E. Sjölin, K. Wåhlén, E. Dungner, B.-M. Leijonhufvud, Y. Widlund and K. Hertel (Department of Medicine Huddinge, Karolinska Institutet, Sweden) is greatly appreciated. We also thank T. Skurk (Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Germany) for advice.

Funding

This study was supported by the Swedish Research Council, NovoNordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation, Karolinska Institutet, SRP Diabetes programme, Åke Wiberg Foundation, Magnus Bergvalls Foundation, Tore Nilsson Foundation, NordForsk (SYSDIET-070014) and NWO Rubicon (825.07.025).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JL and AMLP designed the study. AMLP, BMS, JK, JL, NM, DPA, ID and PA performed experiments, acquired data and/or performed data analysis and interpretation. SLC, AMLP, JL and JK carried out cell system characterisations. AMLP, JK, JL, SLC, GÅ and AVC designed, performed and analysed method development experiments. AP and JL drafted the manuscript. All authors revised the manuscript critically and approved the final version.

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Authors and Affiliations

  1. Department of Medicine Huddinge, Karolinska Institutet, Hälsovägen 7, Novum, 14186, Stockholm, Sweden

    A. M. L. Pettersson, B. M. Stenson, S. Lorente-Cebrián, D. P. Andersson, N. Mejhert, J. Krätzel, G. Åström, I. Dahlman, P. Arner & J. Laurencikiene

  2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    A. V. Chibalin

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  1. A. M. L. Pettersson
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  2. B. M. Stenson
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  3. S. Lorente-Cebrián
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  5. N. Mejhert
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  9. A. V. Chibalin
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  10. P. Arner
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Correspondence to A. M. L. Pettersson or J. Laurencikiene.

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Pettersson, A.M.L., Stenson, B.M., Lorente-Cebrián, S. et al. LXR is a negative regulator of glucose uptake in human adipocytes. Diabetologia 56, 2044–2054 (2013). https://doi.org/10.1007/s00125-013-2954-5

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  • DOI: https://doi.org/10.1007/s00125-013-2954-5

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