Research ArticleCardiologyMetabolism Open Access | 10.1172/jci.insight.184940

Le Phuong Nguyen,1 Wenxin Song,1 Ye Yang,1,2 Anh P. Tran,1 Thomas A. Weston,1 Hyesoo Jung,1 Yiping Tu,1 Paul H. Kim,1 Joonyoung R. Kim,1 Katherine Xie,1 Rachel G. Yu,1 Julia Scheithauer,1 Ashley M. Presnell,1 Michael Ploug,3,4 Gabriel Birrane,5 Hannah Arnold,6 Katarzyna Koltowska,6,7 Maarja A. Mäe,6 Christer Betsholtz,6,8 Liqun He,6 Jeffrey L. Goodwin,9 Anne P. Beigneux,1 Loren G. Fong,1 and Stephen G. Young1,2

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Nguyen, L. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Song, W. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Yang, Y. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Tran, A. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Weston, T. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Jung, H. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Tu, Y. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Kim, P. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Kim, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Xie, K. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Yu, R. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Scheithauer, J. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Presnell, A. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Ploug, M. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Birrane, G. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Arnold, H. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Koltowska, K. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Mäe, M. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Betsholtz, C. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by He, L. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Goodwin, J. in: JCI | PubMed | Google Scholar

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Beigneux, A. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Fong, L. in: JCI | PubMed | Google Scholar |

1Department of Medicine and

2Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

3Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

4Finsen Laboratory, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

5Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

6Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

7Beijer Gene and Neuro Laboratory, Uppsala University, Uppsala, Sweden.

8Department of Medicine-Huddinge, Karolinska Institute Campus Flemingsberg, Huddinge, Sweden.

9Division of Laboratory Animal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY); Phone: 310.825.4997; Email: lfong@mednet.ucla.edu (YGF).

Find articles by Young, S. in: JCI | PubMed | Google Scholar |

Published October 22, 2024 - More info

Published in Volume 9, Issue 20 on October 22, 2024
JCI Insight. 2024;9(20):e184940. https://doi.org/10.1172/jci.insight.184940.
© 2024 Phuong Nguyen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published October 22, 2024 - Version history
Received: July 23, 2024; Accepted: September 10, 2024 View PDF Abstract

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1—the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen—is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.

Introduction

Lipoprotein lipase (LPL) is essential for the intravascular lipolytic processing of triglyceride-rich (TG-rich) lipoproteins (TRLs) (1, 2). In mice, cats, and humans, LPL deficiency markedly impairs TRL processing, resulting in severe hypertriglyceridemia (chylomicronemia) (3-5). In fish and birds (nonmammalian vertebrates, frequently called lower vertebrates), LPL is also important. When chickens were given an intravenous injection of an inhibitory LPL-specific antibody, TG clearance from the plasma was nearly abolished, resulting in severe hypertriglyceridemia (6). Also, LPL deficiency in zebrafish causes severe hypertriglyceridemia, with plasma TG levels over 2,000 mg/dL (7). Not surprisingly, LPL’s primary structure is conserved in vertebrates (e.g., there is 76% amino acid similarity between mouse and chicken LPL and 63% similarity between mouse and zebrafish LPL). Other proteins that regulate LPL-mediated TRL processing (e.g., APOC2, APOC3, ANGPTL4, and ANGPTL3) are also conserved in mammals and lower vertebrates; however, there is a noteworthy exception. GPIHBP1, the endothelial cell (EC) protein that moves LPL to its site of action in the capillary lumen, is present in mammals (including the egg-laying platypus) but is absent in lower vertebrates (8).

In human and mouse hearts, LPL is expressed at high levels in cardiomyocytes, as judged by in situ hybridization (ISH) studies with radioactive probes (9, 10). The LPL secreted by cardiomyocytes is captured by GPIHBP1 on the abluminal plasma membrane of ECs and shuttled to the luminal plasma membrane of capillary ECs (11). In mice, GPIHBP1 is abundant on capillary ECs in the heart, as judged by confocal microscopy, and is undetectable on ECs of venules, arterioles, and larger blood vessels (11-14). LPL is located on capillaries, colocalizing with GPIHBP1. In the mouse heart, much of the LPL that GPIHBP1 moves into capillaries detaches and is captured within the HSPG-rich glycocalyx lining of capillary ECs (14). The LPL within the glycocalyx mediates TRL margination along the luminal surface of capillaries and participates in the lipolytic processing of TRLs (14).

In Gpihbp1–/– mice, LPL is stranded within the interstitial spaces and never reaches the capillary lumen, resulting in severe hypertriglyceridemia (11, 13, 14). The plasma TG levels in chow-fed Gpihbp1–/– mice are 2,500–3,000 mg/dL (11, 15) but can reach 30,000 mg