FTZ alleviates lipid deposition in diabetic kidney disease by AMPK/ACC/SREBP signaling pathway

Fufang Zhenzhu Tiaozhi capsule (FTZ) is a patented traditional Chinese medicine preparation that has been used clinically for nearly 10 years to treat hyperglycemia, hyperlipidemia, and other glucolipid metabolic diseases. Previous studies have shown that FTZ can improve diabetic kidney disease (DKD). However, the role and mechanism of FTZ in reducing renal lipid accumulation in DKD remain unclear. Phosphorylation of Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK), a key regulator of energy homeostasis, inhibits Acetyl-CoA Carboxylase (ACC) signaling, thereby reducing fatty acid synthesis and promoting fatty acid oxidation via carnitine palmitoyltransferase-1 (CPT-1). Sterol regulatory element-binding protein 1 (SREBP-1), a transcription factor, regulates lipid metabolism through fatty acid synthesis. This study investigated the anti-lipid accumulation effect and mechanism of FTZ in vitro and in vivo. Streptozotocin (40 mg/kg/d, i.p. for 5 days, consecutively) combined with a high-fat diet (HFD) were used to induce a DKD model in C57BL/6J mice, followed by FTZ (1, 2 g/kg/d, i.g.) or Losartan (30 mg/kg/d, i.g.) treatments for 12 weeks. High glucose (HG, 30 mM) combined with palmitic-acid (PA, 250 µM) were used to induce HK-2 cells injury, followed by FTZ (25, 50, or 100 µg/ml) or Compound C (an AMPK inhibitor, 10 µM) treatments for 24 h. Results showed that FTZ reduced blood lipids and improved renal function in DKD mice. In addition, compared with the control group, DKD mice and cells exhibited significantly increased lipid deposition. However, the effect of FTZ in alleviating lipid accumulation was reversed by Compound C. Furthermore, FTZ increased p-AMPK, p-ACC and CPT-1 protein expression while decreasing SREBP-1. These results indicate that FTZ effectively protects against lipid accumulation in DKD by regulating the AMPK/ACC/SREBP pathway, inhibiting de novo lipogenesis, providing a novel therapeutic strategy for DKD.