New 'platform' for processing dietary fat discovered

Apr 3 2007

A new "platform" with a crucial role in the body's ability to process and take up fat from the diet has been found, according to a report in the April issue of the journal Cell Metabolism, published by Cell Press.

Researchers discovered a protein that sits on the inner surfaces of capillaries, where it delivers "packages" of dietary fat from the bloodstream to enzymes that prepare them for entry into cells of the body. Once inside cells, the fats are either burned as a rich source of energy or stored for later use.

"We've found a new, very important partner in a process people thought they understood 20 years ago," said Anne Beigneux of the University of California, Los Angeles.

While it is too soon to say whether the finding will have clinical implications in efforts to limit the body's capacity to store fat, for instance, one thing is for certain: "Soon, every biochemistry book will have to be revised," she said.

Dietary fats in mammals are packaged by the intestine into "chylomicrons," which are large triglyceride-rich lipoproteins, Beigneux explained. After reaching the bloodstream, the triglycerides within chylomicrons are broken down by an enzyme found along the surface of capillaries, mainly in the heart, skeletal muscle, and fat tissue. In those tissues, the so-called lipoprotein lipase enzyme is synthesized, secreted, and transported to the capillaries, where the packaged lipids are taken apart.

The fat "bundles" have to be broken down because the lipids are otherwise unable to get across cell membranes, Beigneux added.

The researchers "stumbled onto" a new player in the process after a team at Genentech found mutant mice with severe chylomicronemia, a condition in which the inability to properly process dietary fat leads to high levels of blood triglycerides.

The mice, which lacked a gene called glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, or Gpihbp1, exhibited a striking accumulation of chylomicrons in the plasma, even on a low-fat diet, the researchers report. The animals' deficiency caused their blood plasma to become milky as their blood triglyceride levels skyrocketed. Normally, the lipoprotein-binding protein is found at high levels in heart and adipose tissue, the same tissues that express high levels of the enzyme that breaks chylomicrons down, they report.

The researchers conclude that GPIHBP1 is crucial for chylomicron processing. It is located on the inner surface of the capillary and binds both chylomicrons and the processing enzyme, likely forming a platform for lipid breakdown and playing an important role in the delivery of lipid nutrients to cells.

The findings might have direct implications for patients with chylomicronemia, Beigneux said. The disorder in humans has been linked only to defects in the genes encoding the lipid-degrading enzyme or its cofactor, she explained.

"Now, anybody who has chylomicronemia without one of those mutations should be looked at for a mutation in [this platform protein, GPIHBP1]," she said.