The role of the Niemann-Pick disease, type C1 protein in adipocyte insulin action

Rachael Fletcher; Christopher Gribben; Xiuquan Ma; James G Burchfield; Kristen C Thomas; James R Krycer; David E James; Daniel J Fazakerley

doi:10.1371/journal.pone.0095598

The role of the Niemann-Pick disease, type C1 protein in adipocyte insulin action

PLoS One. 2014 Apr 21;9(4):e95598. doi: 10.1371/journal.pone.0095598. eCollection 2014.

Authors

Rachael Fletcher¹, Christopher Gribben¹, Xiuquan Ma, James G Burchfield¹, Kristen C Thomas¹, James R Krycer², David E James³, Daniel J Fazakerley¹

Affiliations

¹ Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
² Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
³ Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia.

Abstract

The Niemann-Pick disease, type C1 (NPC1) gene encodes a transmembrane protein involved in cholesterol efflux from the lysosome. SNPs within NPC1 have been associated with obesity and type 2 diabetes, and mice heterozygous or null for NPC1 are insulin resistant. However, the molecular mechanism underpinning this association is currently undefined. This study aimed to investigate the effects of inhibiting NPC1 function on insulin action in adipocytes. Both pharmacological and genetic inhibition of NPC1 impaired insulin action. This impairment was evident at the level of insulin signalling and insulin-mediated glucose transport in the short term and decreased GLUT4 expression due to reduced liver X receptor (LXR) transcriptional activity in the long-term. These data show that cholesterol homeostasis through NPC1 plays a crucial role in maintaining insulin action at multiple levels in adipocytes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / drug effects*
Adipocytes / enzymology
Adipocytes / metabolism*
Androstenes / pharmacology
Animals
CHO Cells
Cricetinae
Cricetulus
Enzyme Activation / drug effects
Gene Deletion
Gene Knockout Techniques
Glucose / metabolism
Glucose Transporter Type 4 / genetics
Glucose Transporter Type 4 / metabolism
Insulin / pharmacology*
Intracellular Signaling Peptides and Proteins
Liver X Receptors
Mice
Niemann-Pick C1 Protein
Orphan Nuclear Receptors / metabolism
Phenotype
Protein Transport / drug effects
Proteins / antagonists & inhibitors
Proteins / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects
Transcription, Genetic / drug effects

Substances

Androstenes
Glucose Transporter Type 4
Insulin
Intracellular Signaling Peptides and Proteins
Liver X Receptors
Niemann-Pick C1 Protein
Npc1 protein, mouse
Orphan Nuclear Receptors
Proteins
3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
Proto-Oncogene Proteins c-akt
Glucose

Grants and funding

Medical Research Council/United Kingdom