Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Mardiana Lee, Marina Katerelos, Kurt Gleich, Sandra Galic, Bruce E Kemp, Peter F Mount, David A Power
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 9 Pg. 2326-2336 (09 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29976587 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• Metformin
• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinases (drug effects, metabolism)
• Acetyl-CoA Carboxylase (metabolism)
• Analysis of Variance
• Animals
• Biopsy, Needle
• Cells, Cultured
• Disease Models, Animal
• Humans
• Immunohistochemistry
• Insulin Resistance (physiology)
• Kidney Diseases (metabolism, pathology)
• Kidney Tubules (cytology, metabolism)
• Lipid Metabolism (drug effects)
• Metformin (metabolism, pharmacology)
• Mice
• Mice, Knockout
• Multivariate Analysis
• Oxidation-Reduction (drug effects)
• Phosphorylation
• Random Allocation
• Real-Time Polymerase Chain Reaction