Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes.

Abstract

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.

• Authors: Sarah Brice Russo, Catalin F Baicu, An Van Laer, Tuoyu Geng, Harinath Kasiganesan, Michael R Zile, L Ashley Cowart
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 11 Pg. 3919-30 (Nov 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 23023704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Dietary Fats
• Muscle Proteins
• Sphingolipids
• Myristic Acid
• Sphingosine N-Acyltransferase

Topics

• Animals
• Autophagy (drug effects)
• Diabetes Mellitus, Type 2 (chemically induced, enzymology, pathology)
• Diabetic Cardiomyopathies (chemically induced, enzymology, pathology)
• Dietary Fats (adverse effects, pharmacokinetics)
• Male
• Mice
• Muscle Proteins (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Myristic Acid (adverse effects, pharmacology)
• Sphingolipids (biosynthesis)
• Sphingosine N-Acyltransferase (metabolism)