Homeostatic Remodeling of Mammalian Membranes in Response to Dietary Lipid Perturbations is Essential for Cellular Fitness

Abstract

A major fraction of cellular bioactivity occurs at membranes, with the lipidic matrix constituting a functional, dynamic interface that actively regulates protein activity and cell physiology. Proper membrane functionality requires maintenance of a narrow range of physical properties under challenge from external inputs. The most prominent example of such maintenance is homeostatic adaptation of membrane properties to temperature variation, a fundamental and ubiquitous design feature in ectothermic organisms. However, such responsive membrane adaptation has not been widely investigated in homeotherms. Here, we report that challenging mammalian membrane homeostasis by dietary lipid inputs leads to robust lipidomic remodeling to maintain membrane physical properties. Specifically, supplementation with polyunsaturated fatty acids (PUFAs) leads to rapid and extensive incorporation of the exogenous fats into membrane lipids, inducing a reduction in membrane packing. These effects are rapidly compensated for by upregulation of saturated lipids and cholesterol, via activation of the mammalian sterol regulatory machinery, specifically SREBP pathway, resulting in recovery of membrane fluidity. Inhibition of membrane remodeling results in decreased cellular fitness when membrane homeostasis is challenged by dietary PUFAs. These results reveal a mammalian mechanism for homeostatic membrane remodeling - analogous to homeoviscious adaptation in poikilotherms - wherein cells remodel their membrane lipidomes in response to dietary lipid inputs in order to maintain functional membrane phenotypes.