Does long-term metformin treatment increase cardiac lipoprotein lipase?
Acute activation of adenosine monophosphate-activated protein kinase (AMPK) or jumps in cardiac work increased cardiac endothelial lipoprotein lipase (LPL), yet it is unclear whether chronic AMPK activation maintains this elevated LPL. To activate AMPK chronically, metformin at low (300 mg/kg/d) and high dose (600 mg/kg/d) was administered in drinking water for 14 days. Control, metformin-treated, and 5-amino-imidazole-4-carboxamide riboside (AICAR)-treated (0.5 mmol/L) ex vivo hearts were perfused to investigate uptake of triacylglycerol and cardiac LPL activity. For perfused rat hearts, increased uptake of labeled Intralipid and β-oxidation of Intralipid-fatty acid were noted for both AICAR (P < .05) and high-dose metformin (P < .01). Intralipid incorporation into tissue lipids was decreased by AICAR (P < .05) and increased after high-dose metformin (P < .05), the increase manifest as enhanced triacylglycerol deposition (P < .05). Low-dose metformin did not alter lipid uptake or tissue deposition. Both high-dose metformin and AICAR decreased cardiac acetyl-coenzyme A carboxylase activity (P < .01). Heparin-releasable LPL was increased after treatment with AICAR (P < .05) and high-dose metformin (P < .01). Low-dose metformin did not alter cardiac LPL. High-dose metformin doubled immunoreactive AMPK and phospho-AMPK protein (P < .001) and increased phosphorylation of p38-mitogen-activated protein kinase (P < .05). After heparin pretreatment, the rate of recruitment of LPL to the cardiac endothelium was increased by AICAR (P < .05) but not by high-dose metformin. These data suggest that AMPK activation increased cardiac endothelial LPL, yet acute and chronic activation of AMPK may yield increased LPL through differing mechanisms.
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B152TT Birmingham, United Kingdom. d.hauton@bham.ac.uk
David
D
Hauton
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D014280:Triglycerides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase; C031143:AICA ribonucleotide; D005947:Glucose