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

Abstract

Objective ShcKO mice have low body fat and resist weight gain on a high fat diet, indicating that Shc proteins may influence enzymes involved in β-oxidation. To investigate this idea, the activities of β-oxidation and ketone body metabolism enzymes were measured. Methods The activities of β-oxidation enzymes (acyl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase and ketoacyl-CoA thiolase) in liver and hindlimb skeletal muscle, ketolytic enzymes (acetoacetyl-CoA thiolase, β-hydroxybutyrate dehydrogenase and 3-oxoacid-CoA transferase) in skeletal muscle, and ketogenic enzymes (acetoacetyl-CoA thiolase and β-hydroxybutyrate dehydrogenase) in liver were measured from wild-type and ShcKO mice. Results The activities of β-oxidation enzymes were increased (P < 0.05) 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 < 0.05) 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 < 0.05) in fasted ShcKO mice. Conclusions These studies indicate that the low Shc levels in ShcKO mice result in increased liver and muscle β-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.

p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria

“…1, e and f). This is consistent with previous findings that lipid oxidation is increased in livers of ShcP ϭ ShcKO mice (2), where Shc expression is significantly decreased, and p46Shc is decreased to 20% of wildtype level (3,4). Thus, the increase in palmitate oxidation is a consequence of Shc reduction.…”

“…Resistance in ShcKO Mice-Previous studies indicate that ShcKO mice have multiple health benefits, including lean body mass, resistance to obesity on HFD, and in the context of the Ob/Ob mutation, more longevity on Ob/Ob genotype (4,11), and a trend toward extended longevity on HFD, and significantly increased mitochondrial lipid oxidation activity (1,2), and a global metabolic shift, in which the mitochondrial oxidation of lipids is activated. Data presented here are consistent with a contribution of p46Shc depletion to increased mitochondrial lipid oxidation, and a contribution to the ShcKO mice lean phenotype and healthy aging.…”

“…Shc proteins have three isoforms: p46, p52, and p66, and have major effects on metabolism (1)(2)(3)(4). p52Shc contacts the insulin receptor and regulates the signaling between the IRS1 and Ras pathway (5).…”

“…Briefly, ShcL or ShcProlla mice have a deletion of only the minor p66Shc isoform and have no health benefits: ShcL mice are not lean, do not resist weight gain on high fat diets (HFD), 2 and are not longer-lived on HFD, and do not have improved insulin sensitivity (4). Thus p66Shc deletion by itself does not result in health benefits.…”

“…ShcKO have several health benefits, including a lean phenotype (10), resistance to genetic obesity (11), resistance to high fat diets (HFD) (4) and higher capacity for mitochondria to oxidize lipid iv vitro and iv vivo (2)(3)(4), and a metabolic shift toward increasing mitochondrial lipid oxidation (1,2). Enzymatic activity of mitochondrial thiolase is significantly increased in these ShcKO tissues, which have reduced expression of mitochondrial p46Shc isoform (2).…”