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

Hum Mol Genet. 2010 Feb 15;19(4):597-608. doi: 10.1093/hmg/ddp526. Epub 2009 Dec 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cholesterol / blood
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperlipidemia, Familial Combined / genetics
  • Hyperlipidemia, Familial Combined / metabolism*
  • Lipids / blood*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Upstream Stimulatory Factors / genetics
  • Upstream Stimulatory Factors / metabolism*

Substances

  • Lipids
  • USF1 protein, human
  • Upstream Stimulatory Factors
  • Cholesterol