ROLE OF ACETYL COA CARBOXYLASE IN LIVER LIPID METABOLISM ...

ROLE OF ACETYL COA CARBOXYLASE IN LIV ER LIPID M E T ABO LISM AND INSULIN SIGNA LING

G ENE TIC DISRUPTION O F A C E T Y L C O A C ARBO X Y L ASE PH OSPH O R Y L A T I O N B Y A MP-A C T I V A T E D PR O T E IN K I N ASE IN C R E ASES

LIV ER LIPID A C CUMUL A TION AND INSULIN RESIST ANC E

By KATARINA MARCINKO, B.H.Sc. (H)

A Thesis Submitted to the School of Graduate Studies

In Partial Fulfillment of the Requirements For the Degree

Masters of Science

McMaster University ? Copyright by Katarina Marcinko, July 2011

MASTER OF SCIENCE (2011) (Medical Sciences: Nutrition & Metabolism)

McMaster University Hamilton, Ontario

TITLE:

Genetic Disruption of Acetyl CoA Carboxylase Phosphorylation by AMP-

Activated Protein Kinase Increases Liver Lipid Accumulation and Insulin

Resistance

AUTHOR: Katarina Marcinko, B.H.Sc. (H) (McMaster University)

SUPERVISOR: Gregory R. Steinberg, Ph.D.

NUMBER OF PAGES: xii, 67

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ABSTRA C T In obesity, nonalcoholic fatty liver disease (NAFLD) has been associated with the

development of hepatic insulin resistance; however, the potential causality and molecular mechanisms underlying this relationship are unclear. 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.

To address the above objectives, we examined the metabolic phenotype of C57Bl6 mice with a targeted ACC1 Ser79 to Ala and ACC2 Ser221 to Ala double knockin 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. Fasting blood glucose and insulin were both elevated in ACC DKI mice. Glucose and insulin tolerance were impaired and hyperinsulinemic-euglycaemic clamps revealed that ACC DKIs had liver insulin resistance. Insulin-stimulated glucose disposal rate was also reduced.

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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.

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