Where is the Fat'?

Edward A. Dennis, PhDIn real estate, location is everything. The same might be said of lipids – those crucial cellular fats and oils that serve as building blocks for cells and as key energy sources for the body.

In a paper published in the September issue of the Journal of Lipid Research, a team of scientists, led by researchers at the University of California, San Diego School of Medicine has mapped for the first time the actual locations of specific lipids within a single cell.

"This is groundbreaking analysis," said Edward A. Dennis, PhD, distinguished professor of pharmacology, chemistry and biochemistry at UC San Diego and principal investigator of LIPID MAPS, a national consortium studying the structure and function of lipids. "We've defined not only which lipids are within a particular cell, but also where these lipids are located. That's important because lipids do different things in a cell. They're vital components of membranes. They're involved in communications and signaling, both within cells and between cells. Where they are located – in a cell's nucleus, its mitochondria, membrane or other organelle – is relevant to their function."

And because most serious diseases are linked to specific organelle dysfunction, understanding what lipids do at the subcellular level is essential to elucidating how diseases ranging from atherosclerosis and arthritis to cancer and diabetes work – and how they might be better treated or prevented.

The focus of the lipid mapping was a cultured mouse macrophage or white blood cell, said Dennis, who also serves as editor-in-chief of the Journal of Lipid Research. Alexander Andreyev, PhD, a project scientist in the Dennis lab, extracted and separated organelles of the macrophage using advanced subcellular fractionation techniques. Scientists at collaborating universities then precisely identified and quantified the major lipid categories present with mass spectrometry. More than 220 individual molecular lipid species were identified and analyzed.

The analyses were conducted on macrophages in both resting and activated stages, the latter induced by exposing the cells to a specially synthesized chemical similar to a molecule found in bacteria pathogens. Called KLA, the chemical provokes a signaling cascade inside macrophages, activating their immune system response to infections.