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.

背景患有肾小管间质纤维化（TIF）的肾小管上皮细胞中调节脂肪酸代谢的基因的表达降低，从而降低了脂肪酸氧化（FAO）产生的能量。乙酰辅酶A羧化酶（ACC）是能量敏感的AMP激活蛋白激酶（AMPK）的靶标，是细胞内FAO发生率的主要控制者。二甲双胍具有良好的抗纤维化作用，并能增加AMPK对ACC的磷酸化作用，从而增加FAO含量。

方法我们评估了细胞和小鼠肾病模型中ACC的磷酸化，以及二甲双胍在有和无突变的小鼠中的作用，这些突变会降低ACC的磷酸化。

结果叶酸肾病模型诱导后，在用叶酸处理以模拟细胞损伤的肾小管上皮细胞和野生型（WT）小鼠中，AMPK位点Ser79上ACC的磷酸化均降低。当在具有ACC磷酸化位点的敲入（KI）Ser到Ala突变的小鼠中夸大了这种效应时，与WT相比，脂质积累和纤维化明显增加。在单侧输尿管阻塞模型中证实了ACC磷酸化对纤维化的影响，该模型显示KI小鼠中脂质蓄积和纤维化显着增加。使用二甲双胍与野生型小鼠的纤维化和脂质蓄积显着减少有关。相反，在KI小鼠中，该药物与纤维化恶化有关。

结论这些数据表明，肾脏损伤后ACC磷酸化水平的降低有助于TIF的发展，而二甲双胍在肾脏中的抗纤维化作用需要ACC的磷酸化。