Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.
In obese rodents, excess myocardial lipid accumulation (lipotoxicity) of myocardium may cause cardiomyopathy that in the obese Zucker diabetic fatty (ZDF) fa/fa rat can be prevented by treatment with troglitazone (TGZ). To determine the underlying mechanisms, we measured total 5'-AMP-activated kinase (AMPK) protein and its activated, phosphorylated form, P-AMPK. P-AMPK was significantly reduced in both ZDF fa/fa rat and ob/ob mouse hearts compared with lean, wild-type controls. TGZ treatment of obese ZDF rats, which lowered cardiac lipid content, increased P-AMPK. Expression of protein phosphatase 2C (PP2C), which inactivates AMPK activity by dephosphorylation, was increased in untreated ZDF fa/fa rat hearts, but fell with TGZ treatment, suggesting that PP2C can influence AMPK activity. In cultured myocardiocytes, fatty acids reduced P-AMPK, suggesting a feed-forward effect of lipid overload. Our findings highlight a role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity and provide new insights as to the mechanisms of the liporegulatory disorder leading to lipotoxic cardiomyopathy.
Wang
May-yun
MY
Department of Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. May-yun.Wang@UTSouthwestern.edu
Unger
Roger H
RH
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D051381:Rats; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000263:Adenylate Kinase; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D000077288:Troglitazone; D005947:Glucose