Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Master of Science (MSc)

Department

Medical Sciences

Supervisor

Gregory R. Steinberg

Co-Supervisor

Mark Tarnopolsy, Alison Holloway

Language

English

Committee Member

Mark Tarnopolsy, Alison Holloway

Abstract

In obesity, nonalcoholic fatty liver disease (NAFLD) has been associated with the development of hepatic insulin resistance. Acetyl coA carboxylase (ACC), which exists as two separate isoforms (ACC1 and ACC2), is an important metabolic enzyme which controls the production of the metabolic intermediate malonyl coA, and hence, fat metabolism. AMP-activated protein kinase (AMPK) has been shown to inhibit ACC activity by phosphoryating ACC1 at Ser79 and ACC2 at Ser221. The objectives of this were to determine the physiological importance of AMPK phosphorylation of ACC as it relates to the development of NAFLD and insulin resistance.

We examined the metabolic phenotype of C57Bl6 mice with a targeted ACC1 Ser79 to Ala and ACC2 Ser221 to Ala double knock-in mutation (ACC DKI), which would inhibit AMPK phosphorylation of ACC and compared them to wild-type (WT) mice. Basic body characteristics, assessment of insulin sensitivity, and assessment of liver steatosis were used.

ACC DKI body mass and energy expenditure were not different compared to WT. Liver ACC activity and malonyl coA were higher in ACC DKI mice. The livers of ACC DKI mice displayed greater triacylglycerol accumulation and aggregation of neutrophils. ACC DKI mice were insulin resistant as shown by: higher fasting blood glucose and insulin, glucose and insulin intolerance, liver insulin resistance, and impaired insulin-stimulated glucose disposal rate.

In summary, we have shown that the phosphorylation of ACC1 Ser79 and ACC2 Ser221 is critical for maintaining ACC activity and malonyl coA levels in the liver. The dysregulation of this pathway results in liver fat accumulation and the development of insulin resistance. These studies demonstrate that AMPK phosphorylation of ACC is essential for maintaining metabolic homeostasis.

McMaster University Library

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