Upstream Transcription Factor 1 Influences Plasma Lipid and Metabolic Traits in Mice

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2009 Dec 10

PMID 19995791

Citations 19

Authors

Sulin Wu

Rebecca Mar-Heyming

Eric Z Dugum

Nicholas A Kolaitis

Hongxiu Qi

Paivi Pajukanta

Lawrence W Castellani

Aldons J Lusis

Thomas A Drake

Affiliations

Soon will be listed here.

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.

Citing Articles

Circadian Regulation of Gene Expression and Metabolism in the Liver.

Guan D, Lazar M Semin Liver Dis. 2022; 42(2):113-121.

PMID: 35263797 PMC: 9806798. DOI: 10.1055/a-1792-4240.

Genome-wide scan highlights the role of candidate genes on phenotypic plasticity for age at first calving in Nellore heifers.

Mota L, Lopes F, Fernandes Junior G, Rosa G, Magalhaes A, Carvalheiro R Sci Rep. 2020; 10(1):6481.

PMID: 32296097 PMC: 7160148. DOI: 10.1038/s41598-020-63516-4.

Jain S, Rana A, Jain K, Perla S, Puri N, Kumar A Am J Hypertens. 2018; 31(11):1234-1242.

PMID: 30084918 PMC: 6454504. DOI: 10.1093/ajh/hpy121.

Upstream stimulating factor 1 suppresses autophagy and hepatic lipid droplet catabolism by activating mTOR.

Guo J, Fang W, Chen X, Lin Y, Hu G, Wei J FEBS Lett. 2018; 592(16):2725-2738.

PMID: 30054905 PMC: 6175420. DOI: 10.1002/1873-3468.13203.

Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1).

Noguchi K, Dincman T, Dalton A, Howley B, McCall B, Mohanty B J Biol Chem. 2018; 293(29):11401-11414.

PMID: 29871931 PMC: 6065179. DOI: 10.1074/jbc.RA118.003616.

References

Lusis A, Attie A, Reue K . Metabolic syndrome: from epidemiology to systems biology. Nat Rev Genet. 2008; 9(11):819-30. PMC: 2829312. DOI: 10.1038/nrg2468. View

Lyon H, Emilsson V, Hinney A, Heid I, Lasky-Su J, Zhu X . The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet. 2007; 3(4):e61. PMC: 1857727. DOI: 10.1371/journal.pgen.0030061. View

Pajukanta P, Lilja H, Sinsheimer J, Cantor R, Lusis A, Gentile M . Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet. 2004; 36(4):371-6. DOI: 10.1038/ng1320. View

Tilg H, Moschen A . Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008; 14(3-4):222-31. PMC: 2215762. DOI: 10.2119/2007-00119.Tilg. View

Pajukanta P, Nuotio I, Terwilliger J, Porkka K, Ylitalo K, Pihlajamaki J . Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23. Nat Genet. 1998; 18(4):369-73. DOI: 10.1038/ng0498-369. View

Komulainen K, Alanne M, Auro K, Kilpikari R, Pajukanta P, Saarela J . Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies. PLoS Genet. 2006; 2(5):e69. PMC: 1458962. DOI: 10.1371/journal.pgen.0020069. View

Naukkarinen J, Gentile M, Soro-Paavonen A, Saarela J, Koistinen H, Pajukanta P . USF1 and dyslipidemias: converging evidence for a functional intronic variant. Hum Mol Genet. 2005; 14(17):2595-605. DOI: 10.1093/hmg/ddi294. View

Zeggini E, Damcott C, Hanson R, Karim M, Rayner N, Groves C . Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q. Diabetes. 2006; 55(9):2541-8. DOI: 10.2337/db06-0088. View

Tilg H, Moschen A . Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab. 2008; 19(10):371-9. DOI: 10.1016/j.tem.2008.08.005. View

10.

Karalis K, Giannogonas P, Kodela E, Koutmani Y, Zoumakis M, Teli T . Mechanisms of obesity and related pathology: linking immune responses to metabolic stress. FEBS J. 2009; 276(20):5747-54. DOI: 10.1111/j.1742-4658.2009.07304.x. View

11.

Ng M, Miyake K, So W, Poon E, Lam V, Li J . The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia. 2005; 48(10):2018-24. DOI: 10.1007/s00125-005-1914-0. View

12.

Sirito M, Lin Q, Deng J, Behringer R, Sawadogo M . Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. Proc Natl Acad Sci U S A. 1998; 95(7):3758-63. PMC: 19910. DOI: 10.1073/pnas.95.7.3758. View

13.

Salopuro T, Pulkkinen L, Lindstrom J, Eriksson J, Valle T, Hamalainen H . Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study. Int J Obes (Lond). 2005; 29(10):1245-51. DOI: 10.1038/sj.ijo.0803024. View

14.

Lee J, Lusis A, Pajukanta P . Familial combined hyperlipidemia: upstream transcription factor 1 and beyond. Curr Opin Lipidol. 2006; 17(2):101-9. DOI: 10.1097/01.mol.0000217890.54875.13. View

15.

Ghazalpour A, Doss S, Zhang B, Wang S, Plaisier C, Castellanos R . Integrating genetic and network analysis to characterize genes related to mouse weight. PLoS Genet. 2006; 2(8):e130. PMC: 1550283. DOI: 10.1371/journal.pgen.0020130. View

16.

Wong R, Chang I, Hudak C, Hyun S, Kwan H, Sul H . A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell. 2009; 136(6):1056-72. PMC: 2768498. DOI: 10.1016/j.cell.2008.12.040. View

17.

Auro K, Kristiansson K, Zethelius B, Berne C, Lannfelt L, Taskinen M . USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study. Diabetologia. 2007; 51(3):464-72. DOI: 10.1007/s00125-007-0892-9. View

18.

de Luca C, Olefsky J . Inflammation and insulin resistance. FEBS Lett. 2007; 582(1):97-105. PMC: 2246086. DOI: 10.1016/j.febslet.2007.11.057. View

19.

Meex S, van Vliet-Ostaptchouk J, van der Kallen C, van Greevenbroek M, Schalkwijk C, Feskens E . Upstream transcription factor 1 (USF1) in risk of type 2 diabetes: association study in 2000 Dutch Caucasians. Mol Genet Metab. 2008; 94(3):352-5. DOI: 10.1016/j.ymgme.2008.03.011. View

20.

Yang X, Schadt E, Wang S, Wang H, Arnold A, Ingram-Drake L . Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 2006; 16(8):995-1004. PMC: 1524872. DOI: 10.1101/gr.5217506. View