Inactivating Fatty Acid Synthase Reduces Inflammation by Interfering with Neutrophil Membrane Function

Neutrophils are the most abundant (40% to 75%) type of white blood cells in mammals and form an essential part of the innate immune system. These short-lived and highly motile phagocytes are formed from stem cells in the bone marrow. During the acute phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals in a process called chemotaxis. Low neutrophil counts are termed neutropenia. This can be congenital, or it can develop later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-effect of medication, most prominently chemotherapy or as the result of colonization by intracellular neutrophilic parasites. Neutropenia makes an individual highly susceptible to infections.

Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two identical 272-kDa multifunctional polypeptides, in which substrates are handed from one functional domain to the next. Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids.

Since mice genetically engineered to lack the gene for FAS die in utero, effects of whole-body inhibition of lipogenesis following development have been unknown. And, as inducible global knockout of FAS (iFASKO) in mice is lethal due to a disrupted intestinal barrier and leucopenia, investigators at Washington University School of Medicine (St. Louis, MO, USA) created a line of mice where they could conditionally inactivate FAS activity.

Results published in the January 6, 2014, online edition of the journal Cell Metabolism revealed that conditional loss of FAS was associated with the selective suppression of granulopoiesis (including synthesis of neutrophils) without disrupting granulocytic differentiation. Impaired lipogenesis increased ER (endoplasmic reticulum) stress and apoptosis in neutrophils by preferentially decreasing peroxisome-derived membrane phospholipids containing ether bonds. Inhibiting ether lipid synthesis selectively constrained neutrophil development, revealing an unrecognized pathway in immunometabolism.

"So ether lipids appear to be a very precise target," said senior author Dr. Clay F. Semenkovich, professor of medicine at Washington University School of Medicine. "This may be a pathway to limit inflammation. If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis."

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Washington University School of Medicine