Please use this identifier to cite or link to this item:
|Title:||Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin.|
|Authors:||Lee, Mardiana;Katerelos, Marina;Gleich, Kurt;Galic, Sandra;Kemp, Bruce E;Mount, Peter F;Power, David A|
|Affiliation:||Kidney Laboratory, Department of Nephrology, The University of Melbourne, Heidelberg and Fitzroy, Victoria, Australia|
Department of Medicine, The University of Melbourne, Heidelberg and Fitzroy, Victoria, Australia
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria, Australia
Institute for Breathing and Sleep, Austin Health, Heidelberg, Victoria, Australia
|Citation:||Journal of the American Society of Nephrology : JASN 2018; online first: 5 July|
|Abstract:||Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin's antifibrotic action in the kidney.|
fatty acid oxidation
|Appears in Collections:||Journal articles|
Files in This Item:
There are no files associated with this item.
Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.