In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 45 ( 2017-11-07), p. 11926-11931
Abstract:
Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca 2+ concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca 2+ homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca 2+ acts as a negative regulator of insulin signaling. Chronic intracellular Ca 2+ overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains. Pharmacological approaches showed that elevated intracellular Ca 2+ inhibits insulin-stimulated Akt phosphorylation and abrogates membrane localization of various PH domain proteins such as phospholipase Cδ and insulin receptor substrate 1, suggesting a common mechanism inhibiting the membrane targeting of PH domains. PH domain-lipid overlay assays confirmed that Ca 2+ abolishes the binding of various PH domains to phosphoinositides (PIPs) with two adjacent phosphate groups, such as PI(3,4)P 2 , PI(4,5)P 2 , and PI(3,4,5)P 3 . Finally, thermodynamic analysis of the binding interaction showed that Ca 2+ -mediated inhibition of targeting PH domains to the membrane resulted from the tight binding of Ca 2+ rather than PH domains to PIPs forming Ca 2+ -PIPs. Thus, Ca 2+ -PIPs prevent the recognition of PIPs by PH domains, potentially due to electrostatic repulsion between positively charged side chains in PH domains and the Ca 2+ -PIPs. Our findings provide a mechanistic link between intracellular Ca 2+ dysregulation and Akt inactivation in insulin resistance.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1706489114
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2017
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink
