Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Abstract

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using unbiased lipidomics and proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism maintain membrane homeostasis and adapt to a variable environment.

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

“…At higher concentrations, similar to those measured in plasma from patients on FFA-rich diet 9 , 10 (and at which we found that EA is toxic; Figure 4B ), membrane fluidity was decreased ( Figure 5C ). Exposure to PA led to linear regions of increased rigidity reminiscent of the ER 71 , 72 ( Figure S3E ), while EA induced distinct spherical regions of increased rigidity reminiscent of lipid droplet morphology ( Figure S3E ). These observations are consistent with robust EA incorporation into TAGs ( Figure 5B ).…”

As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

“…RNF145's lipid-modulating effects are intimately linked to its ability to target lipid metabolic enzymes for degradation [75,[79][80][81][82] . Accordingly, RNF145's substrates include the ER-resident lipid hydrolase adiponectin receptor 2 (ADIPOR2) and the cholesterol biosynthetic enzyme HMGCR [75,[79][80][81] .…”

“…ADIPOR2 has an inverted 7-TMD G-protein coupled receptor topology and is structurally and catalytically similar to ceramidases of the CREST superfamily [103][104][105] . Its ceramidase activity may partially explain its function, inducing sphingosine-1-phosphate-mediated activation of PPAR𝛄 or SREBP1 through sphingosine-1-phosphate receptors and transcriptional upregulation of lipid metabolic enzymes including the lipid desaturase SCD1 [82,106] . However, many aspects relating to the molecular function and regulation of ADIPOR2 remain unclear such as how ADIPOR2 senses and responds to PA-induced stress in the absence of an ilgr-2 orthologue [81] .…”

“…ADIPOR2's catalytic activity is required for the processing of dipalmitoyl phospholipids, as deletion of endogenous ADIPOR2 leads to the accumulation of dipalmitoyl phospholipids that was only reversed by expressing catalytically active ADIPOR2 [81,82] . As well as potential ceramidase activity, ADIPOR2 is therefore likely to have a more general lipid hydrolase activity.…”