Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

Stanley M. Walls, Anthony Ross Cammarato, Dale A. Chatfield, Karen Ocorr, Greg L. Harris, Rolf Bodmer

Research output: Contribution to journalArticle

Abstract

Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis.

Original languageEnglish (US)
Pages (from-to)2601-2614
Number of pages14
JournalCell Reports
Volume22
Issue number10
DOIs
StatePublished - Mar 6 2018
Externally publishedYes

Fingerprint

Ceramides
Cardiomyopathies
Proteins
Caspases
Lipogenesis
Mammals
Drosophila
Chemical activation
Maintenance
Lipids
Annexins
Myosins
Metabolism
Dilatation

Keywords

  • Annexin
  • apoptosis
  • diabetic cardiac disease
  • Drosophila
  • FASN
  • heart
  • lipogenesis
  • myriocin
  • sphingolipids
  • Unc-45

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. / Walls, Stanley M.; Cammarato, Anthony Ross; Chatfield, Dale A.; Ocorr, Karen; Harris, Greg L.; Bodmer, Rolf.

In: Cell Reports, Vol. 22, No. 10, 06.03.2018, p. 2601-2614.

Research output: Contribution to journalArticle

Walls, SM, Cammarato, AR, Chatfield, DA, Ocorr, K, Harris, GL & Bodmer, R 2018, 'Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy', Cell Reports, vol. 22, no. 10, pp. 2601-2614. https://doi.org/10.1016/j.celrep.2018.02.034
Walls, Stanley M. ; Cammarato, Anthony Ross ; Chatfield, Dale A. ; Ocorr, Karen ; Harris, Greg L. ; Bodmer, Rolf. / Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. In: Cell Reports. 2018 ; Vol. 22, No. 10. pp. 2601-2614.
@article{6bde1acf0e6a47a6a8a50ef901cf7ecd,
title = "Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy",
abstract = "Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis.",
keywords = "Annexin, apoptosis, diabetic cardiac disease, Drosophila, FASN, heart, lipogenesis, myriocin, sphingolipids, Unc-45",
author = "Walls, {Stanley M.} and Cammarato, {Anthony Ross} and Chatfield, {Dale A.} and Karen Ocorr and Harris, {Greg L.} and Rolf Bodmer",
year = "2018",
month = "3",
day = "6",
doi = "10.1016/j.celrep.2018.02.034",
language = "English (US)",
volume = "22",
pages = "2601--2614",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",

}

TY - JOUR

T1 - Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

AU - Walls, Stanley M.

AU - Cammarato, Anthony Ross

AU - Chatfield, Dale A.

AU - Ocorr, Karen

AU - Harris, Greg L.

AU - Bodmer, Rolf

PY - 2018/3/6

Y1 - 2018/3/6

N2 - Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis.

AB - Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis.

KW - Annexin

KW - apoptosis

KW - diabetic cardiac disease

KW - Drosophila

KW - FASN

KW - heart

KW - lipogenesis

KW - myriocin

KW - sphingolipids

KW - Unc-45

UR - http://www.scopus.com/inward/record.url?scp=85043402178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043402178&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.02.034

DO - 10.1016/j.celrep.2018.02.034

M3 - Article

C2 - 29514098

AN - SCOPUS:85043402178

VL - 22

SP - 2601

EP - 2614

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 10

ER -