Regulation of very-long acyl chain ceramide synthesis by acyl-CoA-binding protein.
Ceramide and more complex sphingolipids constitute a diverse group of lipids that serve important roles as structural entities of biological membranes and as regulators of cellular growth, differentiation, and development. Thus, ceramides are vital players in numerous diseases including metabolic and cardiovascular diseases, as well as neurological disorders. Here we show that acyl-coenzyme A-binding protein (ACBP) potently facilitates very-long acyl chain ceramide synthesis. ACBP increases the activity of ceramide synthase 2 (CerS2) by more than 2-fold and CerS3 activity by 7-fold. ACBP binds very-long-chain acyl-CoA esters, which is required for its ability to stimulate CerS activity. We also show that high-speed liver cytosol from wild-type mice activates CerS3 activity, whereas cytosol from ACBP knock-out mice does not. Consistently, CerS2 and CerS3 activities are significantly reduced in the testes of ACBP-/-mice, concomitant with a significant reduction in long- and very-long-chain ceramide levels. Importantly, we show that ACBP interacts with CerS2 and CerS3. Our data uncover a novel mode of regulation of very-long acyl chain ceramide synthesis by ACBP, which we anticipate is of crucial importance in understanding the regulation of ceramide metabolism in pathogenesis.
From the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Natalia Santos
NS
Ferreira
the Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark, and.
Hanne
H
Engelsby
the Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark, and.
Ditte
D
Neess
the School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0230.
Samuel L
SL
Kelly
From the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Giora
G
Volpert
the School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0230.
Alfred H
AH
Merrill
From the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Anthony H
AH
Futerman
the Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark, and nils.f@bmb.sdu.dk.
Nils J
NJ
Færgeman
D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000096:biosynthesis* / Q000235:genetics; D026261:Diazepam Binding Inhibitor / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D002518:Ceramides; D026261:Diazepam Binding Inhibitor; D005227:Fatty Acids; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C438311:CERS2 protein, human; C583317:CERS3 protein, human; C513562:CerS3 protein, mouse; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase
ACBP; Acyl-CoA; ceramide; ceramide synthase; fatty acid metabolism; lipid binding protein; sphingolipid