Document Detail

Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes.
MedLine Citation:
PMID:  23023704     Owner:  NLM     Status:  MEDLINE    
Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N-acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy.
Sarah Brice Russo; Catalin F Baicu; An Van Laer; Tuoyu Geng; Harinath Kasiganesan; Michael R Zile; L Ashley Cowart
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-12-26     Completed Date:  2013-01-15     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3919-30     Citation Subset:  AIM; IM    
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
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MeSH Terms
Autophagy / drug effects*
Diabetes Mellitus, Type 2 / chemically induced,  enzymology,  pathology
Diabetic Cardiomyopathies / chemically induced,  enzymology*,  pathology
Dietary Fats / adverse effects*,  pharmacokinetics
Muscle Proteins / metabolism*
Myocytes, Cardiac / metabolism*,  pathology
Myristic Acid / adverse effects,  pharmacology
Sphingolipids / biosynthesis
Sphingosine N-Acyltransferase / metabolism*
Grant Support
Reg. No./Substance:
0/Dietary Fats; 0/Muscle Proteins; 0/Sphingolipids; 544-63-8/Myristic Acid; EC N-Acyltransferase

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