Kidney Laboratory, Department of Nephrology, and.
Department of Medicine, The University of Melbourne, Heidelberg and Fitzroy, Victoria, Australia.
J Am Soc Nephrol. 2018 Sep;29(9):2326-2336. doi: 10.1681/ASN.2018010050. Epub 2018 Jul 5.
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.
肾小管上皮细胞中调节脂肪酸代谢的基因表达减少，导致脂肪酸氧化（FAO）产生的能量减少。乙酰辅酶 A 羧化酶（ACC）是细胞内 FAO 速率的主要调节物，是能量感应 AMP 激活蛋白激酶（AMPK）的靶标。二甲双胍具有明确的抗纤维化作用，可增加 AMPK 对 ACC 的磷酸化，从而增加 FAO。
我们评估了细胞和小鼠肾病模型中 ACC 的磷酸化情况，以及在具有或不具有降低 ACC 磷酸化的突变的小鼠中给予二甲双胍的作用。
叶酸处理模拟细胞损伤时，肾小管上皮细胞中 ACC 的 AMPK 位点 Ser79 的磷酸化减少，野生型（WT）小鼠在诱导叶酸肾病模型后也发生了这种情况。当 ACC 磷酸化位点 Ser 突变为 Ala 的 KI 小鼠中这种作用被夸大时，与 WT 相比，脂质积累和纤维化显著增加。单侧输尿管梗阻模型证实了 ACC 磷酸化对纤维化的影响，与 WT 小鼠相比，KI 小鼠的脂质积累和纤维化明显增加。二甲双胍的使用与 WT 小鼠的纤维化和脂质积累显著减少相关。相比之下，在 KI 小鼠中，该药物与纤维化恶化相关。
这些数据表明，肾损伤后 ACC 磷酸化减少导致 TIF 的发生，并且 ACC 的磷酸化是二甲双胍在肾脏中发挥抗纤维化作用所必需的。
