Loss of small heterodimer partner protects against atherosclerosis in apolipoprotein E-deficient mice

Abstract

Small heterodimer partner (SHP) is involved in bile, lipid, and glucose metabolism. The aim of this study was to investigate the effect of SHP on the development of atherosclerosis. Apolipoprotein E knockout (ApoE^-/-) mice were crossed with SHP knockout (SHP^-/-) mice to generate double knockout (ApoE^-/-SHP^-/-) mice. ApoE^-/- and ApoE^-/-SHP^-/- male mice were fed a western diet for 20 weeks. Body weight in ApoE^-/-SHP^-/- mice was significantly lower than that in ApoE^-/- mice (37 ± 1 g vs. 42 ± 1 g, p < 0.01). Loss of SHP in ApoE^-/- mice decreased the size of adipocytes in white adipose tissue and reduced lipid accumulation in the liver. Glucose intolerance was improved in ApoE^-/-SHP^-/- mice as compared with ApoE^-/- mice (p < 0.01). There was no statistical difference in non-high density lipoprotein cholesterol levels between ApoE^-/-SHP^-/- mice and ApoE^-/- mice despite an increase of cholesterol 7α-hydroxylase expression in the liver. The proportion of atherosclerotic lesions in the aorta was significantly lower in ApoE^-/-SHP^-/- mice than in ApoE^-/- mice (2.8 ± 2.0% vs. 9.1 ± 1.9%, p < 0.01). In conclusion, loss of SHP function can prevent atherosclerosis, and resistance to diet-induced obesity is the primary factor contributing to this protective effect.