NEFA-Sensitive Orai1 Expression in Regulation of De Novo Lipogenesis

Non-esterified fatty acids (NEFAs) are important inducers of inflammatory responses and hepatic lipid accumulation, which lead to non-alcoholic fatty liver disease (NAFLD). High plasma NEFA is found in NAFLD patients, and associated with metabolic syndrome and type-2 diabetes. NFκB is known to upregulate Orai1, the Ca2+ channel responsible for store-operated Ca2+ entry. The present study explored the role of NEFA-sensitive NFκB-dependent Orai1 expression in the regulation of lipid synthesis.

BRL-3A rat liver hepatocyte lines were studied in the absence and presence of NEFA. Transcript and protein expression levels of factors involved in lipid synthesis were quantified by quantitative polymerase chain reaction (qPCR) and western blot analyses. Fatty acids were measured by immunofluorescence.

NEFA significantly increased, as indicated by the expression of sterol regulatory element-binding protein 1 (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACC1), Orai1, and NFκB p65 by qPCR and western blot analyses. These effects were reversed by the Orai1 inhibitor, 2-aminoethoxydiphenyl borate, and the NFκB inhibitor, wogonin. Furthermore, SREBP-1c, FAS, ACC1, and Orai1 were significantly decreased by Orai1 silencing.

Taken together, these results demonstrated that NEFA-sensitive NFκB-dependent Orai1 expression regulates de novo lipogenesis.