Endogenous versus exogenous fatty acid availability affects lysosomal acidity and MHC class II expression

S. C. Schweitzer^*, A. M. Reding^*, H. M. Patton^*, T. P. Sullivan^*, C. E. Stubbs, E. Villalobos-Menuey^*, S. A. Huber and M. K. Newell¹^,*

^* Colorado University Institute of Bioenergetics, University of Colorado, Colorado Springs, CO
Department of Biology, University of Colorado, Colorado Springs, CO
Department of Pathology, University of Vermont, Burlington, VT

Published, JLR Papers in Press, August 16, 2006.

^¹ To whom correspondence should be addressed. e-mail: mnewell{at}uccs.edu

Although the immune system, inflammation, and cellular metabolismare linked to diseases associated with dyslipidemias, the mechanism(s)remain unclear. To determine whether there is a mechanisticlink between lipid availability and inflammation/immune activation,we evaluated macrophage cell lines incubated under conditionsof altered exogenous and endogenous lipid availability. Limitingexogenous lipids results in decreased lysosomal acidity anddecreased lysosomal enzymatic activity. Both lysosomal parametersare restored with the addition of oleoyl-CoA, suggesting thatfatty acids play a role in the regulation of lysosomal function.Cell surface expression of major histocompatibility complex(MHC)-encoded molecules is also decreased in the absence ofexogenous lipids. Additionally, we observe decreased ${gamma}$ -interferonstimulation of cell surface MHC class II. Using cerulenin tolimit the endogenous synthesis of fatty acids results in decreasedcell surface expression of MHC class II but does not appearto alter lysosomal acidity, suggesting that lysosomal acidityis dependent on exogenous, but not endogenous, fatty acid availability.Testing these conclusions in an in vivo mouse model, we observedstatistically significant, diet-dependent differences in lysosomalacidity and MHC class II cell surface expression. Collectively,these data demonstrate a mechanistic link between lipid availabilityand early events in the immune response.

Supplementary key words diet • dyslipidemias • inflammation • major histocompatibility complex

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