title: Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2.
abstract: Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.
authors: Dept. of Biomedicine, Molecular Nephrology, Rm. 303, Univ. Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland. andreas.jehle@unibas.ch.
authors: Kapil
authors: K
authors: Kampe
authors: Jonas
authors: J
authors: Sieber
authors: Jana Marina
authors: JM
authors: Orellana
authors: Peter
authors: P
authors: Mundel
authors: Andreas Werner
authors: AW
authors: Jehle
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D012265:Ribonucleotides; D019308:Palmitic Acid; D000620:Aminoimidazole Carboxamide; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide
keywords: AMPK; apoptosis; diabetic nephropathy; palmitic acid; β-oxidation