Shc proteins influence the activities of enzymes involved in fatty acid oxidation and ketogenesis

Objectives. ShcKO mice have low body fat and resist weight gain on a high fat diet, indicating that Shc proteins may influence enzymes involved in beta-oxidation. To investigate this idea, the activities of is-oxidation and ketone body metabolism enzymes were measured. Methods. The activities of beta-oxidation enzymes (acyl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase and ketoacyl-CoA thiolase) in liver and hindlimb skeletal muscle, ketolytic enzymes (acetoacetyl-CoA thiolase, Is-hydroxybutyrate dehydrogenase and 3-oxoacid-CoA transferase) in skeletal muscle, and ketogenic enzymes (acetoacetyl-CoA thiolase and is-hydroxybutyrate dehydrogenase) in liver were measured from wild-type and ShcKO mice. Results. The activities of beta-oxidation enzymes were increased (P<.05) in the ShcKO compared to wild-type mice in the fasted but not the fed state. In contrast, no uniform increases in the ketolytic enzyme activities were observed between ShcKO and wild-type mice. In liver, the activities of ketogenic enzymes were increased (P <.05) in ShcKO compared to wild-type mice in both the fed and fasted states. Levels of phosphorylated hormone sensitive lipase from adipocytes were also increased (P <.05) in fasted ShcKO mice. Conclusion. These studies indicate that the low Shc levels in ShcKO mice result in increased liver and muscle IS-oxidation enzyme activities in response to fasting and induce chronic increases in the activity of liver ketogenic enzymes. Decreases in the level of Shc proteins should be considered as possible contributors to the increase in activity of fatty acid oxidation enzymes in response to physiological conditions which increase reliance on fatty acids as a source of energy. (C) 2012 Elsevier Inc. All rights reserved.