Stephen Young, M.D.UCLA Identifies New Molecule in Body’s Processing of Dietary Fat
Funding from the American Heart Association and NHLBI has enabled UCLA researchers to identify a new molecule that may help regulate the delivery of fats to cells for energy and storage. The finding could lead to a better understanding of how we use fats from the foods we eat.
Digested fats travel to the small intestine, where they are packaged into chylomicrons, which are large, spherical particles filled with triglycerides.
The chylomicrons then travel through the bloodstream delivering triglycerides that feed skeletal muscles and the heart — and to adipose tissue that stores the triglycerides for energy.
As the chylomicroms pass through the inside walls of capillaries, they are caught by molecules called proteoglycans. Proteoglycans hold the chylomicrons steady while the newly-delivered triglycerides are broken down by the enzyme lipoprotein lipase (LpL). The broken-down triglyceride products are then taken up and used by cells.
"Previously we didn't know what molecule in the capillaries facilitated the capture of chylomicrons and facilitated the interaction with lipoprotein lipase," said Dr. Stephen Young, study author and investigator at the David Geffen School of Medicine at UCLA. "We think that we've found the missing piece of the puzzle."
Dr. Young has an impressive history of AHA funding by the Western States Affiliate and the National Center, from 1985 to 1994, that laid the groundwork for these studies.
The investigators discovered that a protein called glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) may be the missing link.
They found that mice deficient in GPIHBP1 develop very high triglyceride levels, even on a normal diet, demonstrating that fats in the bloodstream are not readily metabolized in the absence of GPIHBP1. These mice also had much higher levels of chylomicrons in the bloodstream than normal mice and they had grossly milky plasma, reflecting very large amounts of triglycerides in the blood.
The scientists predicted that if GPIHBP1 were involved in the processing of chylomicrons in the bloodstream, then the protein would be made by endothelial cells of the capillaries, where the breakdown of triglycerides takes place. And, indeed, they did find that GPIHBP1 is expressed highly and exclusively on the endothelial cells of capillaries of heart, adipose tissue and skeletal muscle.
Interestingly, they found that this protein was absent from the brain, which mainly uses glucose for energy. "These differences suggest that endothelial cells may play an active role in regulating the delivery of lipid nutrients to different tissues," said Anne Beigneux, who is also an AHA awardee and author of the study.
The next step for this team will be to determine if GPIHBP1 provides the only binding site for chylomicrons and lipoprotein lipase within capillaries. Investigators also want to define the molecular basis for how GPIHBP1 binds to chylomicron particles.