Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

Publication date: 6 March 2018
Source:Cell Reports, Volume 22, Issue 10
Author(s): Stanley M. Walls, Anthony Cammarato, Dale A. Chatfield, Karen Ocorr, Greg L. Harris, Rolf Bodmer
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.

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Teaser

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.


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