The adiponectin receptor AdipoR2 and its Caenorhabditis elegans homolog PAQR-2 prevent membrane rigidification by exogenous saturated fatty acids

Abstract

Dietary fatty acids can be incorporated directly into phospholipids. This poses a specific challenge to cellular membranes since their composition, hence properties, could greatly vary with different diets. That vast variations in diets are tolerated therefore implies the existence of regulatory mechanisms that monitor and regulate membrane compositions. Here we show that the adiponectin receptor AdipoR2, and its C. elegans homolog PAQR-2, are essential to counter the membrane rigidifying effects of exogenously provided saturated fatty acids. In particular, we use dietary supplements or mutated E. coli as food, together with direct measurements of membrane fluidity and composition, to show that diets containing a high ratio of saturated to monounsaturated fatty acids cause membrane rigidity and lethality in the paqr-2 mutant. We also show that mammalian cells in which AdipoR2 has been knocked-down by siRNA are unable to prevent the membrane-rigidifying effects of palmitic acid. We conclude that the PAQR-2 and AdipoR2 proteins share an evolutionarily conserved function that maintains membrane fluidity in the presence of exogenous saturated fatty acids.

Membrane Fluidity Is Regulated Cell Nonautonomously byCaenorhabditis elegansPAQR-2 and Its Mammalian Homolog AdipoR2

“…THE Caenorhabditis elegans protein PAQR-2 is a member of the PAQR protein family and is homologous to the antidiabetic mammalian proteins AdipoR1 and AdipoR2 ( Svensson et al 2011 ; Devkota et al 2017 ). Various lines of evidence, ranging from crystal structure determination to C. elegans genetics, suggest that PAQR-2 and its AdipoR homologs have seven transmembrane domains with their N terminus in the cytosol ( Svensson et al 2011 ; Tanabe et al 2015 ; Vasiliauskaité-Brooks et al 2017 ), have a hydrolases activity capable of using ceramides as substrates ( Holland et al 2011 ; Pei et al 2011 ; Vasiliauskaité-Brooks et al 2017 ) and are required for membrane homeostasis during cold adaptation ( Svensson et al 2011 ; Svensk et al 2013 ) or upon a rigidifying challenge by exogenous saturated fatty acids (SFAs) ( Svensk et al 2016 ; Devkota et al 2017 ). The paqr-2 mutant is also intolerant of glucose because it is readily converted to membrane-rigidifying SFAs by the dietary Escherichia coli ( Devkota et al 2017 ).…”

“…Additionally, the paqr-2 mutant has reduced brood size, length, locomotion rate and life span, and a withered tail tip ( Svensson et al 2011 ). All of these phenotypes seem secondary to a primary membrane homeostasis defect since they are abrogated by mutations that result in increased unsaturated fatty acids (UFAs) production, by the inclusion of UFAs in the diet or by supplementation of the culture plate with membrane-fluidizing concentrations of nonionic detergents (NP-40 or Triton X-100) ( Svensk et al 2013 , 2016 ; Devkota et al 2017 ). Also, suppression of the paqr-2 mutant phenotypes is invariably associated with improved membrane fluidity, which we have measured in vivo using fluorescence recovery after photobleaching (FRAP) ( Svensk et al 2016 ; Devkota et al 2017 ).…”

C. elegans Mediator 15 permits low temperature-induced longevity via regulation of lipid and protein homeostasis

“…Thus, a reduction in the UFA/SFA ratio at low temperatures may increase the rigidity of membranes to a harmful level, which in turn may shorten lifespan. A recent study has demonstrated that feeding worms with glucose or glycolysis metabolites increases their membrane rigidity by altering bacterial metabolism (Devkota et al, 2017). However, we showed that feeding C. elegans with a glucoseenriched diet along with dead bacteria also shortened lifespan substantially at low temperature ( Fig.…”

“…5D), suggesting that MDT-15 and NHR-49 act together to increase the longevity at low temperature. Fourth, glucose-enriched diets, which decrease the UFA/SFA ratio while increasing the overall fat levels (Devkota et al, 2017;Lee et al, 2015;Pang et al, 2014), also substantially shortened longevity at 15°C (Fig. 5E, F) but not at 25°C ( Fig.…”

AdipoR2 is Essential for Membrane Lipid Homeostasis in Response to Dietary Saturated Fats

“…Asterisks are used in the figures to indicate various degrees of significance, where *: p<0.05; **: p<0.01; and ***: p<0.001. In healthy cells, AdipoR2 responds to increased membrane rigidification by signalling to promote the expression of desaturases and other lipid metabolism genes (5), leading to increased levels of UFAs available for incorporation into phospholipids (6) and normalization of membrane fluidity (7). Some cells can also sequester SFAs into lipid droplets in the form of TAGs (8).…”