Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice.
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.
Wu
Sulin
S
Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
Mar-Heyming
Rebecca
R
Dugum
Eric Z
EZ
Kolaitis
Nicholas A
NA
Qi
Hongxiu
H
Pajukanta
Päivi
P
Castellani
Lawrence W
LW
Lusis
Aldons J
AJ
Drake
Thomas A
TA
D000818:Animals; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
D008055:Lipids; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D002784:Cholesterol