Homeoviscous Adaptation in Mammalian Cell Membranes in Response to Dietary Lipid Perturbations

Abstract

Membrane functionality requires maintenance of a narrow range of physical properties which are constantly challenged by dietary sources with potentially profound physiological consequences. We report that differentiation of human mesenchymal stem cells (MSCs) into osteoblasts or adipocytes results in extensive remodeling of the plasma membrane (PM), producing cell-specific membrane compositions and biophysical properties. Supplementation with docosahexaenoic acid, a lipid component characteristic of osteoblast membranes, induced broad lipidomic remodeling in MSCs and potentiated osteogenic differentiation. In addition to these effects on differentiation, we observed that lipidomic remodeling comprises a homeostatic response to dietary lipid challenge of membrane physical properties. Observations in prokaryotes and other non-thermoregulatory organisms have established that proper membrane functionality requires maintenance of a narrow range of physical properties under challenge from external inputs. Homeostatic adaptation of membrane properties to temperature variation is a fundamental and ubiquitous design feature in ectothermic organisms; however, such responsive membrane adaptation has not been observed in mammals. Here, we show that polyunsaturated fatty acids are rapidly and extensively incorporated into membrane lipids and induce a reduction in membrane packing. Both in vitro and in vivo, we observe a rapid compensation by upregulation of saturated lipids and cholesterol and suppression of other polyunsaturated lipids. These responses are mediated by activation of the classical mammalian sterol regulatory machinery, and ultimately result in recovery of membrane fluidity. Inhibition of membrane remodeling results in decreased cellular fitness when membrane homeostasis is challenged by dietary lipids. This suggests that mammals have maintained an essential mechanism for membrane homeostasis, analogous to homeoviscous adaptation; however, mammalian cells remodel their membrane lipidomes in response to dietary lipid inputs, rather than temperature, in order to maintain functional membrane phenotypes.