Mice lacking global Stap1 expression do not manifest hypercholesterolemia
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RESEARCH ARTICLE
Open Access
Mice lacking global Stap1 expression do not manifest hypercholesterolemia Babunageswararao Kanuri1, Vincent Fong1, April Haller2, David Y. Hui2 and Shailendra B. Patel1*
Abstract Background: Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1−/−) were characterized under standard chow and a 42% kcal western diet (WD). Methods: Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons. Results: Surprisingly, Stap1−/− mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1+/+ mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice. Conclusion: These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia. Keywords: STAP1, Autosomal dominant familial hypercholesterolemia, Familial hypercholesterolemia 4, B-cells, Western diet, Fast performance liquid chromatography
Background Familial hypercholesterolemia (FH) is a widely prevalent congenital metabolic disorder characterized by substantially elevated circulatory low density lipoprotein cholesterol (LDL-C) and accelerated cardiovascular events [1, 2]. Autosomal dominant inherited hypercholesterolemia (ADH) accounts for a major proportion of the FH cases worldwide with mutations most commonly reported in low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) [3–5]. However, a number of patients classified * Correspondence: [email protected] 1 Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA Full list of author information is available at the end of the article
as having familial hypercholesterolemia 4 (FH4), demonstrate the ADH phenotype despite having no mutations in these genes [6]. Initial studies involving these patients reported mutations in genes coding for signal-transducing adaptor family member 1 (STAP1) [6–8]. STAP1 (MIM#604298), also called B-cell antigen receptor downstream signaling 1 protein (BRDG1) or stem cell adaptor protein 1, was first discovered in immune cells with the highest expression documented in
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