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