MicroRNA-155 deficiency leads to decreased atherosclerosis, increased white adipose tissue obesity, and non-alcoholic fatty liver disease a novel mouse model of obesity paradox

Anthony Virtue, Candice Johnson, Jahaira Lopez-Pastraña, Ying Shao, Hangfei Fu, Xinyuan Li, Ya Feng Li, Ying Yin, Jietang Mai, Victor Rizzo, Michael Tordoff, Zsolt Bagi, Huimin Shan, Xiaohua Jiang, Hong Wang, Xiao Feng Yang

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE-/-) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE-/- mice, and miR-155 deficiency in apoE-/- mice inhibits atherosclerosis; 2) apoE-/-/miR-155-/- (double knockout (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.

Original languageEnglish (US)
Pages (from-to)1267-1287
Number of pages21
JournalJournal of Biological Chemistry
Volume292
Issue number4
DOIs
StatePublished - Jan 27 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Virtue, A., Johnson, C., Lopez-Pastraña, J., Shao, Y., Fu, H., Li, X., Li, Y. F., Yin, Y., Mai, J., Rizzo, V., Tordoff, M., Bagi, Z., Shan, H., Jiang, X., Wang, H., & Yang, X. F. (2017). MicroRNA-155 deficiency leads to decreased atherosclerosis, increased white adipose tissue obesity, and non-alcoholic fatty liver disease a novel mouse model of obesity paradox. Journal of Biological Chemistry, 292(4), 1267-1287. https://doi.org/10.1074/jbc.M116.739839