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The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

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Abstract

Here we report that the transcription factor cyclic AMP–responsive element–binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H–deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 (encoding apolipoproteins C2, A4 and A5, respectively) and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism.

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Figure 1: Creb3l3−/− mice show hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by Lpl.
Figure 2: CREB-H controls genes involved in triglyceride metabolism, and mutations of CREB3L3 are associated with human hypertriglyceridemia.

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Acknowledgements

We thank B. Zhai and S. Gygi for mass spectrometry analysis, K. Sigrist for assistance with the development of transgenic mice, R. Hassell for assistance with genomic DNA sequencing, B. Monia (Isis Innovation) for Apoc3-specific antibody and D. Cohen for invaluable suggestions and comments on the manuscript. The research was supported by the Harvard University Accelerator Fund (L.H.G.), a Howard Hughes Medical Institute (HHMI) fellowship (P.G.), the Harvard Digestive Disease Center, US National Institutes of Health grant P30 DK34845 (A.-H.L.), US National Institutes of Health grant DK082448 (L.H.G.) and grants from the American Heart Association (A.-H.L. and J.H.L.), Canadian Institutes for Health Research and Genome Canada through the Ontario Genomics Institute.

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Jung Hoon Lee, Petros Giannikopoulos, Laurie H Glimcher & Ann-Hwee Lee

  2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Stephen A Duncan

  3. Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    Jian Wang, Christopher T Johansen & Robert A Hegele

  4. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Jonathan D Brown & Jorge Plutzky

  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Laurie H Glimcher & Ann-Hwee Lee

  6. Ragon Institute of MGH, MIT and Harvard, Harvard Medical School, Boston, Massachusetts, USA

    Laurie H Glimcher

Authors
  1. Jung Hoon Lee
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  2. Petros Giannikopoulos
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  3. Stephen A Duncan
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  4. Jian Wang
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  5. Christopher T Johansen
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  6. Jonathan D Brown
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  7. Jorge Plutzky
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  8. Robert A Hegele
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  9. Laurie H Glimcher
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  10. Ann-Hwee Lee
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Contributions

A.-H.L. designed the experiments. J.H.L. performed in vivo experiments in Creb3l3−/− mice and mutational analysis of CREB-H protein. A.-H.L. and P.G. generated and characterized CREB-H(N)-transgenic mice. J.D.B. performed post-heparin LPL assays. J.W. and C.T.J. performed sequencing experiments. S.A.D. provided Creb3l3−/− mice. A.-H.L., L.H.G., R.A.H. and J.P. analyzed the data. A.-H.L., L.H.G. and R.A.H. wrote the manuscript.

Corresponding authors

Correspondence to Laurie H Glimcher or Ann-Hwee Lee.

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Competing interests

L.H.G. holds equity in and is on the corporate board of directors of Bristol-Myers Squibb.

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Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1842 kb)

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Lee, J., Giannikopoulos, P., Duncan, S. et al. The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism. Nat Med 17, 812–815 (2011). https://doi.org/10.1038/nm.2347

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  • DOI: https://doi.org/10.1038/nm.2347

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