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Stearoyl-CoA desaturase : role in metabolic syndrome, atherosclerosis and inflammation MacDonald, Marcia Leigh

Abstract

Combination of the risk factors obesity, insulin resistance, dyslipidemia, and hypertension, often described as the "metabolic syndrome," increases the risk of developing diabetes and cardiovascular disease. Stearoyl-coenzyme A desaturase (SCD) activity has been implicated in the metabolic syndrome; however, earlier studies on the beneficial metabolic effects of SCD1 deficiency have been confined to normolipidemic mice, and the role of SCD in the context of atherosclerosis has not been examined. The primary purpose of this thesis was to investigate the effect of decreased SCD activity on susceptibility to atherosclerosis in mice. Thus, the overarching hypothesis driving the work was that SCD activity is atherogenic. As well, we examined the effect of absence of SCD1 on features of the metabolic syndrome and chronic inflammation in a mouse model of familial hyperlipidemia. An additional objective was to determine the effect of SCD1 deficiency on dextran sulfate sodium (DSS)-induced acute colitis with DSS dosing adjusted to account for genotypic differences in fluid consumption. These studies help us understand SCD functions in lipid metabolism and evaluate its attractiveness as a therapeutic target for the metabolic syndrome or atherosclerosis. After the Scd1ab-J mutation was characterized, mice carrying this allele were crossed with the low density lipoprotein receptor (LDLR)-deficient mouse strain. Features of the metabolic syndrome and atherosclerotic lesion area were evaluated in mice challenged with a Western diet for twelve weeks. In studies of colonic inflammation, wild-type controls were treated with 3.5% DSS for 5 days to induce moderately severe colitis, while the concentration of DSS given to SCD1-deficient mice was lowered to 2.5% to control for increased fluid consumption. Despite an antiatherogenic metabolic profile, SCD1 deficiency increased atherosclerosis in hyperlipidemic LDLR-deficient mice. Absence of SCD1 also led to chronic inflammation of the skin and increased plasma inflammatory markers, but did not accelerate inflammation in DSS-induced acute colitis when DSS intake was controlled. These findings reinforce the crucial role of chronic inflammation in promoting atherosclerosis, even in the presence of antiatherogenic metabolic characteristics, and suggest that inflammation must be closely monitored in studies of SCD inhibitors for treatment of the metabolic syndrome in humans.

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