Fatty acid transport protein 2 interacts with ceramide synthase 2 to promote ceramide synthesis

Kim, Jiyoon L; Mestre, Beatriz; Malitsky, Sergey; Itkin, Maxim; Kupervaser, Meital; Futerman, Anthony H.

doi:10.1016/j.jbc.2022.101735

Cited by 9 publications

(15 citation statements)

References 54 publications

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“…This suggests that additional, currently-unknown mechanisms of CerS regulation exist, which may depend on a number of factors. CerS interact with a number of proteins in vitro and in vivo [ 35 , 36 ], and moreover are regulated by a number of post-translational mechanisms, including phosphorylation [ 33 , 34 ]. It may be that these mechanisms are not required for CerS activity in vitro , but that their in vivo function affects CerS activity in such a way that cannot be reproduced in vitro .…”

Section: Resultsmentioning

confidence: 99%

“…It may be that these mechanisms are not required for CerS activity in vitro , but that their in vivo function affects CerS activity in such a way that cannot be reproduced in vitro . For example, FATP2 which interacts with CerS2 in mouse liver, increases ceramide levels upon overexpression in Hek293T cells [ 36 ], and a number of proteins involved in regulation of acyl CoA, such as ACSL5 [ 37 ] and ELOVL1 also interact with the CerS in vivo [ 38 ]. Together, our findings suggest that novel approaches will be required to determine the role of functional domains of CerS in vivo , at least in mouse models, which is likely to lead to further refinement of our understanding of their complex modes of regulation.…”

Section: Resultsmentioning

confidence: 99%

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Generation of a ceramide synthase 6 mouse lacking the DDRSDIE C-terminal motif

et al. 2022

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The important membrane lipid, ceramide, is generated by a family of homologous enzymes, the ceramide synthases (CerSs), multi-spanning membrane proteins located in the endoplasmic reticulum. Six CerS isoforms exist in mammals with each using a subset of acyl-CoAs for (dihydro)ceramide synthesis. A number of mice have been generated in which one or other CerS has been genetically manipulated, including complete knock-outs, with each displaying phenotypes concomitant with the expression levels of the CerS in question and the presumed biological function of the ceramide species that it generates. We recently described a short C-terminal motif in the CerS which is involved in CerS dimer formation; deleting this motif had no effect on the ability of the CerS to synthesize ceramide in vitro. In the current study, we generated a CerS6 mouse using CRISPR-Cas9, in which the DDRSDIE motif was replaced by ADAAAIA. While levels of CerS6ADAAAIA expression were unaffected in the CerS6ADAAAIA mouse, and CerS6ADAAAIA was able to generate C16-ceramide in vitro, ceramide levels were significantly reduced in the CerS6ADAAAIA mouse, suggesting that replacing this motif affects an as-yet unknown mechanism of regulation of ceramide synthesis via the DDRSDIE motif in vivo. Crossing CerS6ADAAAIA mice with CerS5 null mice led to generation of viable mice in which C16-ceramide levels were reduced by up to 90%, suggesting that depletion of C16-ceramide levels is compensated for by other ceramide species with different acyl chain lengths.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Generation of a ceramide synthase 6 mouse lacking the DDRSDIE C-terminal motif

et al. 2022

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“…The residual FA transporters are incompletely characterized; FATP3 is also expressed along the apical proximal tubule membrane, though not nearly as abundantly as FATP2 (Khan et al, unpublished observations). In addition to mediating bulk FA uptake, FATP2 physically interacts with ceramide synthase 2, and contributes catalytically to increased synthesis of potentially cytotoxic ceramides and dihydroceramides [ 79 ].…”

Section: Lipotoxicity Of Podocytesmentioning

confidence: 99%

The Contribution of Lipotoxicity to Diabetic Kidney Disease

Schelling

2022

Cells

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Lipotoxicity is a fundamental pathophysiologic mechanism in diabetes and non-alcoholic fatty liver disease and is now increasingly recognized in diabetic kidney disease (DKD) pathogenesis. This review highlights lipotoxicity pathways in the podocyte and proximal tubule cell, which are arguably the two most critical sites in the nephron for DKD. The discussion focuses on membrane transporters and lipid droplets, which represent potential therapeutic targets, as well as current and developing pharmacologic approaches to reduce renal lipotoxicity.

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“…CerS can be regulated by multiple mechanisms, such as dimerization [51], phosphorylation [50], glycosylation [44] and interaction with other proteins including some related to the generation, supply and elongation of acyl-CoAs [52]. Indeed, it is becoming apparent that the multiple modes of regulation of the six mammalian CerS, along with the numerous pathways that need to feed into the CerS to supply substrates and regulate their activity, reveal an extraordinary level of complexity.…”

Section: Ceramide Synthasementioning

confidence: 99%

The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

2022

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Modern cell membranes contain a bewildering complexity of lipids, among them sphingolipids (SLs). Advances in mass spectrometry have led to the realization that the number and combinatorial complexity of lipids, including SLs, is much greater than previously appreciated. SLs are generated de novo by four enzymes, namely serine palmitoyltransferase, 3-ketodihydrosphingosine reductase, ceramide synthase and dihydroceramide D4-desaturase 1. Some of these enzymes depend on the availability of specific substrates and cofactors, which are themselves supplied by other complex metabolic pathways. The evolution of these four enzymes is poorly understood and likely depends on the co-evolution of the metabolic pathways that supply the other essential reaction components. Here, we introduce the concept of the 'anteome', from the Latin ante ('before') to describe the network of metabolic ('omic') pathways that must have converged in order for these pathways to co-evolve and permit SL synthesis. We also suggest that the current origin of life and evolutionary models lack appropriate experimental support to explain the appearance of this complex metabolic pathway and its anteome.

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Fatty acid transport protein 2 interacts with ceramide synthase 2 to promote ceramide synthesis

Cited by 9 publications

References 54 publications

Generation of a ceramide synthase 6 mouse lacking the DDRSDIE C-terminal motif

Generation of a ceramide synthase 6 mouse lacking the DDRSDIE C-terminal motif

The Contribution of Lipotoxicity to Diabetic Kidney Disease

The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

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