Lipidomic and biophysical homeostasis of mammalian membranes in response to dietary lipids is essential for cellular fitness

Abstract

24Biological membranes form the functional, dynamic interface that hosts a major fraction of all cellular 25 bioactivity. Proper membrane physiology requires maintenance of a narrow range of physicochemical 26properties, which must be buffered from external perturbations. While homeostatic adaptation of 27 membrane fluidity to temperature variation is a ubiquitous design feature of ectothermic organisms, such 28 responsive membrane adaptation to external inputs has not been directly observed in mammals. Here, we 29 report that challenging mammalian membrane homeostasis by dietary lipids leads to robust lipidomic 30 remodeling to preserve membrane physical properties. Specifically, exogenous polyunsaturated fatty acids 31 (PUFAs) are rapidly and extensively incorporated into membrane lipids, inducing a reduction in 32 membrane packing. These effects are rapidly compensated both in culture and in vivo by lipidome-wide 33 remodeling, most notably upregulation of saturated lipids and cholesterol. These lipidomic changes result 34 in recovery of membrane packing and permeability. This lipidomic and biophysical compensation is 35 mediated in part by lipid regulatory machinery, whose pharmacological or genetic abrogation results in 36 cytotoxicity when membrane homeostasis is challenged by dietary lipids. These results reveal an essential 37 mammalian mechanism for membrane homeostasis wherein lipidome remodeling in response to dietary 38 lipid inputs preserves functional membrane phenotypes. 39 40 Importantly, the physicochemical properties of the lipid matrix are key contributors to membrane 47 physiology. A canonical example is membrane viscosity, which determines protein diffusivity, and thus 48 protein-protein interaction frequency. Another is membrane permeability, which governs the diffusion of 49 solutes into and out of the cytosol. Numerous other membrane physical parameters can determine protein 50 behavior, including but not limited to fluidity, permeability, curvature, tension, packing, bilayer thickness, 51 and lateral compartmentalization 2-12 . 52Because of their central role in protein function, effective maintenance of membrane properties is essential 53 for cell survival in complex and variable environments. In ectothermic (i.e. non-thermoregulating) 54 3 organisms, a pervasive challenge to membrane homeostasis comes from temperature variations. Low 55 temperature reduces the motion of lipid acyl chains, causing membranes to laterally contract, stiffen, and 56 become more viscous 13 . Organisms across the tree of life, from prokaryotes to ectothermic animals, 57 respond to such perturbations by tuning membrane lipid composition, down-regulating tightly packing 58 lipids (e.g. containing saturated acyl chains) and up-regulating more loosely packed ones containing 59 unsaturations or methylations in their lipid tails [13][14][15] . This response was termed 'homeoviscous 60 adaptation', as these lipid changes result in remarkable constancy in membrane fluidity in spite of variable 61 growth conditions 13,...

Low membrane fluidity triggers lipid phase separation and protein segregation in vivo

“…Later, membranes and membrane proteins evolved to fulfill a multitude of cellular functions such as transport, respiration, and morphogenesis. Since the physicochemical state of biological membranes is highly sensitive to changes in the environment including temperature, osmolarity, salinity or pH (Ernst et al, 2016;Hazel, 1995), careful homeostatic regulation of key membrane parameters such as thickness or fluidity is vital for cell function (Ernst et al, 2016;Harayama and Riezman, 2018;Levental et al, 2018;Parsons and Rock, 2013;Silhavy et al, 2010).…”

Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations

“…Daily doses of 450 mg of n-3 LCPUFAs/kg for seven consecutive days have been associated with multiple positive health effects and the prevention of several nontransmissible diseases (45), including IRI to the liver (13).These effects are exerted through development of antioxidant and anti-inflammatory responses (Fig. 1B), besides their role in membrane adaptation to perturbations in composition as a central requirement for cellular homeostasis (46). The antioxidant effect is achieved by J 3isoprostane production due to spontaneous DHA peroxidation promoting Nrf2 activation (Fig.…”