Niemann–Pick type C (NPC) disease is a neuro-visceral cholesterol storage disorder caused by mutations in the NPC-1 or NPC-2 gene. In the present paper, we studied IR (insulin receptor) activation and the plasma-membrane lipid assembly in primary hepatocytes from control and NPC1–/– mice. We have previously reported that, in hepatocytes, IR activation is dependent on cholesterol–sphingolipid rafts [Vainio, Heino, Mansson, Fredman, Kuismanen, Vaarala and Ikonen (2002) EMBO Rep. 3, 95–100]. We found that, in NPC hepatocytes, IR levels were up-regulated and the receptor activation was compromised. Defective IR activation was reproduced in isolated NPC plasma-membrane preparations, which displayed an increased cholesterol content and saturation of major phospholipids. The NPC plasma membranes were less fluid than control membranes as indicated by increased DPH (1,6-diphenyl-1,3,5-hexatriene) fluorescence anisotropy values. Both in NPC hepatocytes and plasma-membrane fractions, the association of IR with low-density DRMs (detergent-resistant membranes) was increased. Moreover, the detergent resistance of both cholesterol and phosphatidylcholine were increased in NPC membranes. Finally, cholesterol removal inhibited IR activation in control membranes but restored IR activation in NPC membranes. Taken together, the results reveal a lipid imbalance in the NPC hepatocyte, which increases lipid ordering in the plasma membrane, alters the properties of lipid rafts and interferes with the function of a raft-associated plasma-membrane receptor. Such a mechanism may participate in the pathogenesis of NPC disease and contribute to insulin resistance in other disorders of lipid metabolism.
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Research Article|
October 25 2005
Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes
Saara Vainio;
Saara Vainio
*National Public Health Institute, Helsinki, Finland
†Institute of Biotechnology, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
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Igor Bykov;
Igor Bykov
*National Public Health Institute, Helsinki, Finland
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Martin Hermansson;
Martin Hermansson
‡Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
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Eija Jokitalo;
Eija Jokitalo
†Institute of Biotechnology, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
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Pentti Somerharju;
Pentti Somerharju
‡Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
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Elina Ikonen
Elina Ikonen
1
†Institute of Biotechnology, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
‡Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, FIN-00014, Finland
1To whom correspondence should be addressed (email elina.ikonen@helsinki.fi).
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Publisher: Portland Press Ltd
Received:
March 18 2005
Revision Received:
June 02 2005
Accepted:
June 09 2005
Accepted Manuscript online:
June 09 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 391 (3): 465–472.
Article history
Received:
March 18 2005
Revision Received:
June 02 2005
Accepted:
June 09 2005
Accepted Manuscript online:
June 09 2005
Citation
Saara Vainio, Igor Bykov, Martin Hermansson, Eija Jokitalo, Pentti Somerharju, Elina Ikonen; Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes. Biochem J 1 November 2005; 391 (3): 465–472. doi: https://doi.org/10.1042/BJ20050460
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