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Knockdown of ATP citrate lyase in pancreatic beta cells does not inhibit insulin secretion or glucose flux and implicates the acetoacetate pathway in insulin secretion.

Abstract：

OBJECTIVE:Glucose-stimulated insulin secretion in pancreatic beta cells requires metabolic signals including the generation of glucose-derived short chain acyl-CoAs in the cytosol from mitochondrially-derived metabolites. One concept of insulin secretion is that ATP citrate lyase generates short chain acyl-CoAs in the cytosol from mitochondrially-derived citrate. Of these, malonyl-CoA, is believed to be an important signal in insulin secretion. Malonyl-CoA is also a precursor for lipids. Our recent evidence suggested that, in the mitochondria of beta cells, glucose-derived pyruvate can be metabolized to acetoacetate that is exported to the cytosol and metabolized to the same short chain acyl-CoAs and fatty acids that can be derived from citrate. We tested for redundancy of the citrate pathway. METHODS:We inhibited ATP citrate lyase activity using hydroxycitrate as well as studying a stable cell line generated with shRNA knockdown of ATP citrate lyase in the pancreatic beta cell line INS-1 832/13. RESULTS:In both instances glucose-stimulated insulin release was not inhibited. Mass spectrometry analysis showed that the flux of carbon from [U-(13)C]glucose and/or [U-(13)C]α-ketoisocaproic acid (KIC) into short chain acyl-CoAs in cells with hydroxycitrate-inhibited ATP citrate lyase or in the cell line with stable severe (>90%) shRNA knockdown of ATP citrate lyase was similar to the controls. Both (13)C-glucose and (13)C-KIC introduced substantial (13)C labeling into acetyl-CoA, malonyl-CoA, and HMG-CoA under both conditions. Glucose flux into fatty acids was not affected by ATP citrate lyase knockdown. CONCLUSION:The results establish the involvement of the acetoacetate pathway in insulin secretion in pancreatic beta cells.

journal_name

Mol Metab

journal_title

Molecular metabolism

authors

El Azzouny M,Longacre MJ,Ansari IH,Kennedy RT,Burant CF,MacDonald MJ

doi

10.1016/j.molmet.2016.07.011

subject

Has Abstract

pub_date

2016-08-08 00:00:00

pages

980-987

issue

10

issn

2212-8778

pii

S2212-8778(16)30104-1

journal_volume

5

pub_type

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