Abstract
Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.
Highlights
Remedy the systemic and tissue hyperlipidemia associated with these disorders
The former enzyme plays a prominent role in synthesis of new fatty acids from glucose and other fuels, whereas the latter is thought to participate in regulation of fatty acid oxidation via production of a mitochondrialocalized pool of malonyl-CoA that regulates carnitine palmitoyltransferase 1 (CPT1)
Less clear is the role of endogenously produced long-chain acyl-CoAs in the regulation of insulin secretion [21], because expression of malonyl-CoA decarboxylase in -cells decreases de novo lipogenesis with no effect on glucose-stimulated insulin secretion (GSIS) in the absence of fatty acids [22,23,24]
Summary
Remedy the systemic and tissue hyperlipidemia associated with these disorders. if drugs that target ACC2 are to be used safely, two important concerns must be addressed. Current ACC inhibitors do not discriminate between the ACC1 and ACC2 isoforms The former enzyme plays a prominent role in synthesis of new fatty acids from glucose and other fuels, whereas the latter is thought to participate in regulation of fatty acid oxidation via production of a mitochondrialocalized pool of malonyl-CoA that regulates carnitine palmitoyltransferase 1 (CPT1). Chronic Suppression of ACC1 Impairs Insulin Secretion metabolism [8], pyruvate cycling [9], the NADH shuttle system [10], de novo lipogenesis/long-chain acyl-CoAs [11, 12], and NADPH production [13,14,15]. The goal of the present study was to investigate the effects of pharmacologic and molecular suppression of ACC1 activity on insulin secretion and metabolism in both insulinoma cell lines and primary rat islets
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