Health + Behavior

UCLA Identifies New Molecule Involved in the Body’s Processing of Dietary Fat


UCLA investigators have identified a new molecule that mayhelp regulate the delivery of fats to cells for energy and storage.

Published in the April issue of the journal Cell Metabolism,the finding could lead to a better understanding of how we utilize fats fromthe foods we eat.

"We thought that we had figured out how the body digests anduses fats, but we have identified a completely new player in the game," said thestudy's author Anne Beigneux, assistant investigator at the David Geffen Schoolof Medicine at UCLA.

Digested fats travel to the small intestine, where they arepackaged into chylomicrons, which are large, spherical particles filled withtriglycerides.

Chylomicrons then travel through the bloodstream and delivertriglycerides to the skeletal muscles and heart — tissues that are hungry forfuel — or to adipose tissue for energy storage.Molecules called proteoglycans, attached to the inside walls ofcapillaries, wait like baseball players with their mitts open, poised to catchthe passing chylomicrons.

Proteoglycans hold the chylomicrons steady while thetriglycerides are broken down or hydrolyzed by the enzyme lipoprotein lipase(LpL). The triglyceride breakdown products are then taken up and used by cells.

"Previously we didn't know what molecule in the capillariesfacilitated the capture of chylomicrons and facilitated the interaction withlipoprotein lipase," said Dr. Stephen Young, study author and investigator atthe David Geffen School of Medicine at UCLA. "We think that we've found themissing piece of the puzzle."

Investigators discovered that a protein calledglycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein1 (GPIHBP1) may be the missing link.

Scientists found that mice deficient in GPIHBP1 develop veryhigh triglyceride levels, even on a normal diet, demonstrating that fats in thebloodstream are not readily metabolized in the absence of GPIHBP1.

Laboratory tests confirmed that GPIHBP1-deficient mice hadmuch higher levels of chylomicrons inthe bloodstream than normal mice. The GPIHBP1-deficient mice had grossly milkyplasma, reflecting very large amounts of triglycerides in the blood.

"These findings indicate a defect in the breakdown ofchylomicrons in mice that don't have GPIHBP1," Beigneux said.

Investigators predicted that if GPIHBP1 were involved in theprocessing of chylomicrons in the bloodstream, then the protein would be madeby endothelial cells of capillaries, where the breakdown of triglycerides takesplace. Indeed, microscopy showed that GPIHBP1 is expressed highly andexclusively on the endothelial cells of capillaries of heart, adipose tissueand skeletal muscle.

Interestingly, scientists found that this protein was absentfrom the brain, which mainly uses glucose for energy.

"These differences suggest that endothelial cells may playan active role in regulating the delivery of lipid nutrients to differenttissues," Beigneux said.

Experiments with cultured cells revealed that GPIHBP1 bindsboth chylomicrons and lipoprotein lipase, suggesting GPIHBP1 is a key platformfor the processing of chylomicrons.

The next step, according to investigators, will be todetermine if GPIHBP1 provides the only binding site for chylomicrons andlipoprotein lipase within capillaries. In addition, investigators would like todefine the molecular basis for how GPIHBP1 binds to chylomicron particles.

The study was funded by the American Heart Association andthe National Heart, Lung, and Blood Institute.

Other authors include: Brandon S.J. Davies, Peter Gin,Michael M. Weinstein, Emily Farber, Xin Qiao and Loren Fong of the division ofcardiology at the David Geffen School of Medicine at UCLA; Franklin Peale, StuartBunting and Fred de Sauvage of Genentech, San Francisco; Rosemary L. Walzem ofthe department of poultry science and the department of nutrition and foodsciences at Texas A&M University; Jinny S. Wong of the University ofCalifornia, San Francisco; William S. Blaner of Columbia University'sdepartment of medicine, New York; Zhi-Ming Ding of Lexicon Genetics, Texas;Kristan Melford and Robert O. Ryan of Children's Hospital Oakland ResearchInstitute, California; and Andre Bensadoun of the division of nutritional sciencesat Cornell University, New York.



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