About Our Research
Stephen G. Young, along with two UCLA faculty colleagues (Anne P. Beigneux and Loren G. Fong), identified a GPI-anchored endothelial cell protein, GPIHBP1, that is required for the intravascular processing of triglyceride-rich lipoproteins (TRLs). We went on to show that GPIHBP1 binds lipoprotein lipase (LPL) in the interstitial spaces and shuttles it across endothelial cells to its site of action in the capillary lumen. In the absence of GPIHBP1, LPL remains stranded in the interstitial spaces, and TRL processing is severely impaired. GPIHBP1 is also required for the margination of TRLs along capillaries (allowing LPL-mediated triglyceride processing to proceed). In the absence of GPIHBP1, lipoproteins never stop along capillaries. Along with Michael Ploug (Copenhagen, Denmark), we showed that the binding of GPIHBP1 to LPL preserves the structural integrity of LPL as well as its enzymatic activity.
The consequences of LPL deficiency and GPIHBP1 deficiency in humans are identical—impaired TRL processing and severe hypertriglyceridemia. We have identified multiple GPIHBP1 mutations associated with hypertriglyceridemia; all of the mutations abolish the ability of GPIHBP1 to bind LPL. We also identified LPL mutations that abolish the ability of LPL to bind to GPIHBP1. Recently, our group, along with Katsuyuki Nakajima, showed that some acquired cases of hypertriglyceridemia are caused by GPIHBP1 autoantibodies. GPIHBP1 autoantibodies block the ability of GPIHBP1 to capture LPL and escort the enzyme to the capillary lumen.
Dr. Young is an elected member of the National Academy of Sciences.
Principal Investigator
Stephen G. Young
sgyoung@mednet.ucla.edu
Collaborators
Loren Fong
lfong@mednet.ucla.edu
Anne Beigneux
abeigneux@mednet.ucla.edu
Recently Published
The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing | PNAS Oct 23rd, 2023
News & Awards
- Stephen G. Young, M.D. was elected to the US National Academy of Sciences (2016) and was elected as a Corresponding Member Abroad of the Austrian Academy of Sciences (2022).
- Stephen G. Young, M.D. was elected as an Inaugural Fellow of the American Society of Biochemistry and Molecular Biology (the only UCLA scientist—and the sole physician-scientist—to be honored as an ASBMB fellow).
- Ye Yang and colleagues have a newly in press “Images in Lipid Research” article for the Journal of Lipid Research, published November 2023.
- Caitlyn Tran, a UCLA undergraduate student in our laboratory 2019-2023, is now a medical student at Georgetown University’s School of Medicine.
- Wenxin Song, Ph.D. received an American Heart Association Postdoctoral Fellowship (April 2023) for the second time, with both of her fellowship applications scoring <3 percentile.
- Loren G. Fong, Ph.D. submitted an NIH R01 grant on molecular mechanisms of hypertriglyceridemia and received a percentile score of 3%.
- Loren G. Fong, Ph.D., Anne P. Beigneux, Ph.D., and Stephen G. Young have been funded by a Leducq International Network grant on plasma triglyceride metabolism, which will start January 2024.
- Ye Yang published a paper in The Journal of Clinical Investigation (October 2023) showing that the hypertriglyceridemia associated with APOA5 deficiency results from reduced amounts of lipoprotein lipase in capillaries.
- Wenxin Song, Ph.D. published a paper in the Proceedings of the National Academy of Sciences USA (October 2023) showing that much of the lipoprotein lipase that is transported into capillaries by GPIHBP1 detaches and enters the glycocalyx, where it functions to hydrolyze triglycerides in the plasma.
- Joonyoung Kim published a paper in Nucleus (September 2023) that deciphered the molecular mechanism for a truncated lamin A in a commonly used strain of lamin A/C knockout mice.