Journal Article

Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice

Sulin Wu, Rebecca Mar-Heyming, Eric Z. Dugum, Nicholas A. Kolaitis, Hongxiu Qi, Päivi Pajukanta, Lawrence W. Castellani, Aldons J. Lusis and Thomas A. Drake

in Human Molecular Genetics

Volume 19, issue 4, pages 597-608
Published in print February 2010 | ISSN: 0964-6906
Published online December 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp526
Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice

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Upstream transcription factor 1 (USF1) has been associated with familial combined hyperlipidemia, the metabolic syndrome, and related conditions, but the mechanisms involved are unknown. In this study, we report validation of Usf1 as a causal gene of cholesterol homeostasis, insulin sensitivity and body composition in mouse models using several complementary approaches and identify associated pathways and gene expression network modules. Over-expression of human USF1 in both transgenic mice and mice with transient liver-specific over-expression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL/VLDL cholesterol and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic over-expression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2-centered module. In all three mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes.

Journal Article.  6822 words.  Illustrated.

Subjects: Genetics and Genomics

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