Research ArticleMetabolismVascular biology Open Access | 10.1172/JCI172600

Ye Yang,1,2 Anne P. Beigneux,1 Wenxin Song,1 Le Phuong Nguyen,1 Hyesoo Jung,1 Yiping Tu,1 Thomas A. Weston,1 Caitlyn M. Tran,1 Katherine Xie,1 Rachel G. Yu,1 Anh P. Tran,1 Kazuya Miyashita,3 Katsuyuki Nakajima,3 Masami Murakami,3 Yan Q. Chen,4 Eugene Y. Zhen,4 Joonyoung R. Kim,1 Paul H. Kim,1 Gabriel Birrane,5 Peter Tontonoz,6 Michael Ploug,7,8 Robert J. Konrad,4 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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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

1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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

1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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

1Department of Medicine and

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

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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.

3Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.

4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

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

6Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.

7Finsen Laboratory, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

8Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Address correspondence to: Stephen G. Young or Loren G. Fong, Department of Medicine, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA. Phone: 310.825.4934; Email: sgyoung@mednet.ucla.edu (SGY). Email: lfong@mednet.ucla.edu (LGF).

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Published October 12, 2023 - More info

Published in Volume 133, Issue 23 on December 1, 2023
J Clin Invest. 2023;133(23):e172600. https://doi.org/10.1172/JCI172600.
© 2023 Yang 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 12, 2023 - Version history
Received: May 26, 2023; Accepted: October 5, 2023 View PDF Abstract

Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5–/– mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5–/– mice. LPL levels in the postheparin plasma were also lower in Apoa5–/– mice. We suspected that a recent biochemical observation — that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity — could be related to the low intracapillary LPL levels in Apoa5–/– mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5–/– mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5–/– mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.

Graphical Abstract Introduction

Apolipoprotein AV (APOA5), uncovered by comparative sequencing of the mouse and human APOAI/CIII/AIV gene cluster (1), has substantial effects on plasma triglyceride (TG) metabolism. Apoa5–/– mice have markedly elevated plasma TG levels, with a striking accumulation of large-diameter TG-rich lipoproteins (TRLs) (2, 3). In contrast, overexpression of human APOA5 lowers plasma TG levels (1). APOA5 is clinically important; APOA5 mutations result in hypertriglyceridemia (4–9) and an increased risk of coronary heart disease (4, 10, 11).

APOA5 deficiency retards the processing of TRLs (2, 3, 12). For example, the processing and clearance of TRLs are delayed in Apoa5–/– mice, as judged by studies involving chylomicrons labeled with [14C]palmitate and [3H]cholesterol (12). Despite considerable effort, however, the mechanisms by which APOA5 deficiency impairs TRL processing have remained unclear. One idea has been that APOA5 interacts directly with lipoprotein lipase (LPL) and activates its TG hydrolase activity (13–15), but several studies did not detect any effect of APOA5 on LPL catalytic activity (16–18). Another idea has been that APOA5, by virtue of its positively charged heparin-binding domain, increases the margination of TRLs along the luminal surface of capillaries by promoting interactions with heparan sulfate proteoglycans (HSPGs) (16, 17). This idea, however, is open to question because the levels of APOA5 in the plasma are extremely low, such that only a small percentage of TRLs contain a single molecule of APOA5 (19–21). Also, the margination of TRLs along capillaries appears to be mediated by LPL on the luminal surface of capillaries (22).

Because LPL is so crucial for TRL processing and because TRL processing is impaired in the setting of APOA5 deficiency, several studies have examined a link between APOA5 deficiency and LPL expression (2, 5–9, 12, 17). Each of these studies has drawn inferences about intravascular LPL levels from an indirect method — measuring levels of TG hydrolase activity in the plasma after a bolus of heparin. The inferences have been remarkably inconsistent. In humans with APOA5 mutations, 3 research groups found that postheparin LPL activity levels were low (5–7), while 2 groups concluded that the LPL levels were normal (8, 9). Studies of LPL levels in Apoa5–/– mice also have been inconsistent. In 1 study, LPL activity levels in the postheparin plasma were reported to be low (12), whereas in other studies the LPL activity levels were judged to be normal (2,