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An investigation of the potential role of PKC isoforms in the regulation of acetyl-CoA carboxylase-1 Collins, Susan Elizabeth


Acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the first committed step in de novo fatty acid synthesis. Although the enzyme is activated in response to insulin, the mechanism of activation is unclear. In adipose tissue, ACC is phosphorylated on a distinct site, the ‘I-site’, in a PI3K-dependent manner following insulin stimulation but the kinase responsible has not yet been identified. This thesis describes work done to test the role of the atypical PKC isozymes as potential ACC kinases. Analysis of kinase expression revealed that PKC isozymes delta, zeta, and mu (PKD) were highly expressed in rat white adipose tissue. Of nine purified PKC isozymes tested in vitro, PKC-zeta phosporylated ACC most efficiently, but the stoichiometry of phosphorylation was still very low. In adipocytes, the PKC inhibitor Ro 31-8220 accelerated the activation of ACC in response to insulin, suggesting that a target of the compound is normally involved in the inhibition of ACC activation. Another PKC inhibitor, Go 6983, had no effect. The two compounds have similar potency against PKC isozymes, with the exception of PKC-betal and -betall which are more sensitive to Ro 31-8220. AMPK, which has been reported to inhibit ACC in adipose tissue, is also inhibited by Ro 31-8220 in vitro, but probably not in adipocytes. This indicates that some kinase other than AMPK is responsible for inhibition of ACC in adipocytes. The delay in ACC activation following insulin stimulation may represent an important control in glucose utilization. In addition, the more rapid activation of ACC following treatment of adipocytes with Ro 31-8220 indicates that a target of this compound is responsible for the delay.

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