title: Palmitate diet-induced loss of cardiac caveolin-3: a novel mechanism for lipid-induced contractile dysfunction.
abstract: Obesity is associated with an increased risk of cardiomyopathy, and mechanisms linking the underlying risk and dietary factors are not well understood. We tested the hypothesis that dietary intake of saturated fat increases the levels of sphingolipids, namely ceramide and sphingomyelin in cardiac cell membranes that disrupt caveolae, specialized membrane micro-domains and important for cellular signaling. C57BL/6 mice were fed two high-fat diets: palmitate diet (21% total fat, 47% is palmitate), and MCT diet (21% medium-chain triglycerides, no palmitate). We established that high-palmitate feeding for 12 weeks leads to 40% and 50% increases in ceramide and sphingomyelin, respectively, in cellular membranes. Concomitant with sphingolipid accumulation, we observed a 40% reduction in systolic contractile performance. To explore the relationship of increased sphingolipids with caveolins, we analyzed caveolin protein levels and intracellular localization in isolated cardiomyocytes. In normal cardiomyocytes, caveolin-1 and caveolin-3 co-localize at the plasma membrane and the T-tubule system. However, mice maintained on palmitate lost 80% of caveolin-3, mainly from the T-tubule system. Mice maintained on MCT diet had a 90% reduction in caveolin-1. These data show that caveolin isoforms are sensitive to the lipid environment. These data are further supported by similar findings in human cardiac tissue samples from non-obese, obese, non-obese cardiomyopathic, and obese cardiomyopathic patients. To further elucidate the contractile dysfunction associated with the loss of caveolin-3, we determined the localization of the ryanodine receptor and found lower expression and loss of the striated appearance of this protein. We suggest that palmitate-induced loss of caveolin-3 results in cardiac contractile dysfunction via a defect in calcium-induced calcium release.
authors.affiliation: Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, United States of America.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Knowles
authors.forename: Martina
authors.initials: M
authors.lastname: Cebova
authors.forename: Ilka M
authors.initials: IM
authors.lastname: Pinz
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D051244:Caveolin 3 / Q000172:deficiency / Q000235:genetics*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D019308:Palmitic Acid / Q000009:adverse effects*; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics; D013109:Sphingomyelins / Q000378:metabolism; D014280:Triglycerides / Q000008:administration & dosage
chemical_list: D051244:Caveolin 3; D002518:Ceramides; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D013109:Sphingomyelins; D014280:Triglycerides; D019308:Palmitic Acid; D002118:Calcium