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Autoantibodies against GPIHBP1 protein found to cause hypertriglyceridemia
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Researchers have determined a cause for severe hypertriglyceridemia and chylomicronemia.
Stephen G. Young, MD, distinguished professor of medicine and human genetics at the University of California, Los Angeles, and colleagues found six patients with chylomicronemia whose plasma contained autoantibodies against GPIHBP1. They then tested whether the autoantibodies blocked the binding between lipoprotein lipase and GPIHBP1.
Young and colleagues, including Anne P. Beigneux, PhD, and Loren G. Fong, PhD, also from UCLA, wrote in The New England Journal of Medicine that the GPIHBP1 autoantibodies prevented GPIHBP1 from binding lipoprotein lipase, “thereby interfering with lipoprotein lipase–mediated processing of triglyceride-rich lipoproteins in the bloodstream and causing severe hypertriglyceridemia.” Two patients responded to treatment with immunosuppressive agents.
Young spoke to Cardiology Today about the significance of the findings and how they might translate to better treatment for patients with hypertriglyceridemia.
Q: Why did your team decide to pursue this line of research?
A: For more than 50 years, no one really knew how lipoprotein lipase, which is made by myocytes and adipocytes, reached its site of action along the luminal surface of capillary endothelial cells. No one really knew how lipoprotein reached the capillary lumen or how it was bound to endothelial cells. Our laboratory solved that mystery. We found that there is a dedicated endothelial cell protein, GPIHBP1, that binds lipoprotein lipase on the basolateral surface of capillary endothelial cells and shuttles it across endothelial cells to its site of action in the capillary lumen. When this protein is absent as a result of genetic mutation — when there is a deficiency of GPIHBP1 — lipoprotein lipase remains in the subendothelial spaces. It never reaches the lumen of capillaries, where it needs to be to cleave the triglycerides in the bloodstream. Without GPIHBP1, lipoprotein lipase is trapped in the interstitial spaces; the triglycerides in the bloodstream cannot be processed; and the result is severe hypertriglyceridemia.
Q: What are the most important implications of the NEJM study?
A: The NEJM paper shows that GPIHBP1 autoantibodies cause severe chylomicronemia —exactly like a genetic deficiency of GPIHBP1. The GPIHBP1 autoantibodies bind to GPIHBP1 on capillary endothelial cells, preventing GPIHBP1 from binding lipoprotein lipase; the result is an absence of lipoprotein lipase in the capillary lumen and severe hypertriglyceridemia.
This project was a team effort, with important collaborators across the world. Many authors worked hard — it wasn’t just me and Anne P. Beigneux, the first author. We are grateful to all of our co-authors, in particular Loren G. Fong from UCLA and Katuyuki Nakashima, PhD, from Gunma University in Maebashi, Japan.
Q: How might this research be used to help patients with hypertriglyceridemia?
A: People had been studying high plasma triglycerides for more than 50 years, but no one had realized that autoantibodies against GPIHBP1 cause disease. In the clinic, there are many patients who have hypertriglyceridemia from unknown causes. GPIHPB1 autoantibodies represent a new cause of disease. It’s an important cause because most of the patients we identified had severe hypertriglyceridemia, which can lead to pancreatitis, which can be fatal. Also, it appears that the “GPIHBP1 autoantibody syndrome” can be treated. Several of the patients that we presented in the NEJM paper had been treated with immunosuppressive drugs, and their hypertriglyceridemia got better, with their triglycerides falling to normal levels. More work needs to be done to define the best forms of therapy for this disorder, but the preliminary observations suggest that immunosuppressive drugs can be helpful. It’s a newly recognized, potentially life-threatening human disease, and it is a disease that appears to be treatable.
Q: Where should the research go from here?
A: There are three issues to address. No. 1, the patient population in the NEJM paper was highly selected. Now, we need to figure out the prevalence of the GPIHBP1 autoantibody syndrome in patients with severe hypertriglyceridemia.
No. 2, we have to figure out if there are cases of mild to moderate hypertriglyceridemia that are caused by lower levels of GPIHBP1 autoantibodies. There’s every reason to believe that there probably are some patients with mild hypertriglyceridemia who simply have lower levels of GPIHBP1 autoantibodies.
No. 3, once more patients with the GPIHBP1 autoantibody syndrome are identified, we need to follow their response to treatment. What is the best form of treatment? What treatments are effective in lowering GPIHBP1 autoantibodies in the blood — and in lowering plasma triglyceride levels? What is the correlation between the loss of autoantibodies during treatment and plasma triglyceride levels? Now that we recognize the existence of the GPIHBP1 autoantibody syndrome and have simple diagnostic methods, we should be able to address all of these issues. – by Erik Swain
Reference:
Beigneux AP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611930.
Disclosure: Young reports receiving personal fees from Shire and being named on a potential patent to be filed relating to GPIHBP1 assays. Please see the full study for a list of the other researchers’ relevant financial disclosures.