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Research Article

Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho

Ting Fu, Sung-E Choi, Dong-Hyun Kim, Sunmi Seok, Kelly M. Suino-Powell, H. Eric Xu, and Jongsook Kim Kemper
PNAS first published September 17, 2012; https://doi.org/10.1073/pnas.1205951109
Ting Fu
aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and
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Sung-E Choi
aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and
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Dong-Hyun Kim
aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and
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Sunmi Seok
aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and
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Kelly M. Suino-Powell
bLaboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI 49503
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H. Eric Xu
bLaboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI 49503
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Jongsook Kim Kemper
aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and
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  • For correspondence: jongsook@illinois.edu
  1. Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 24, 2012 (received for review April 8, 2012)

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Abstract

MicroRNA-34a (miR-34a) is the most highly elevated hepatic miR in obese mice and is also substantially elevated in patients who have steatosis, but its role in obesity and metabolic dysfunction remains unclear. After a meal, FGF19 is secreted from the ileum; binds to a hepatic membrane receptor complex, FGF19 receptor 4 and coreceptor β-Klotho (βKL); and mediates postprandial responses under physiological conditions, but hepatic responses to FGF19 signaling were shown to be impaired in patients with steatosis. Here, we show an unexpected functional link between aberrantly elevated miR-34a and impaired βKL/FGF19 signaling in obesity. In vitro studies show that miR-34a down-regulates βKL by binding to the 3′ UTR of βKL mRNA. Adenoviral-mediated overexpression of miR-34a in mice decreased hepatic βKL levels, impaired FGF19-activated ERK and glycogen synthase kinase signaling, and altered expression of FGF19 metabolic target genes. Consistent with these results, βKL levels were decreased and hepatic responses to FGF19 were severely impaired in dietary obese mice that have elevated miR-34a. Remarkably, in vivo antisense inhibition of miR-34a in obese mice partially restored βKL levels and improved FGF19 target gene expression and metabolic outcomes, including decreased liver fat. Further, anti–miR-34a treatment in primary hepatocytes of obese mice restored FGF19-activated ERK and glycogen synthase kinase signaling in a βKL-dependent manner. These results indicate that aberrantly elevated miR-34a in obesity attenuates hepatic FGF19 signaling by directly targeting βKL. The miR-34a/βKL/FGF19 axis may present unique therapeutic targets for FGF19-related human diseases, including metabolic disorders and cancer.

  • Cyp7a1
  • FGF15
  • bile acids
  • hepatic metabolism

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: jongsook{at}illinois.edu.
  • Author contributions: T.F. and J.K.K. designed research; T.F., S.C., D.-H.K., and S.M.S. performed research; K.M.S.-P. and H.E.X. contributed new reagents/analytic tools; T.F., S.C., and S.M.S. analyzed data; and J.K.K. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1205951109/-/DCSupplemental.

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miR-34a targets β-Klotho/FGF19 signaling
Ting Fu, Sung-E Choi, Dong-Hyun Kim, Sunmi Seok, Kelly M. Suino-Powell, H. Eric Xu, Jongsook Kim Kemper
Proceedings of the National Academy of Sciences Sep 2012, 201205951; DOI: 10.1073/pnas.1205951109

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miR-34a targets β-Klotho/FGF19 signaling
Ting Fu, Sung-E Choi, Dong-Hyun Kim, Sunmi Seok, Kelly M. Suino-Powell, H. Eric Xu, Jongsook Kim Kemper
Proceedings of the National Academy of Sciences Sep 2012, 201205951; DOI: 10.1073/pnas.1205951109
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