Renal Transporter and Molecular Signaling Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand.
Arch Pharm Res. 2023 May;46(5):408-422. doi: 10.1007/s12272-023-01439-0. Epub 2023 Mar 26.
Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.
长期摄入高脂肪饮食（HFD）会破坏胰岛素信号和脂质代谢。这种破坏会导致胰岛素抵抗、血脂异常，随后由于 AMP 激活的蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体-α（PPARα）或 AMPK/PPARα 途径失活，导致肾功能障碍。我们研究了二甲双胍通过调节高脂肪饮食诱导的胰岛素抵抗大鼠中 AMPK 调节的 PPARα 依赖性途径对预防肾功能障碍的影响。雄性 Wistar 大鼠喂食 HFD 16 周以诱导胰岛素抵抗。在确认胰岛素抵抗后，给予二甲双胍（30mg/kg）或吉非贝齐（50mg/kg）口服 8 周。HF 大鼠出现胰岛素抵抗、血脂异常、脂质堆积和肾脏损伤的证据。HF 大鼠的脂质氧化、能量代谢和肾脏有机阴离子转运蛋白 3（Oat3）表达和功能受损。二甲双胍可刺激 AMPK/PPARα 途径，抑制固醇调节元件结合转录因子 1（SREBP1）和脂肪酸合酶（FAS）信号（SREBP1/FAS），从而调节脂质代谢。与吉非贝齐治疗相比，二甲双胍治疗更有效地减轻了高脂肪饮食引起的肾脏炎症标志物和肾脏纤维化表达。有趣的是，二甲双胍和吉非贝齐治疗后改善了肾脏 Oat3 功能和表达以及肾脏损伤。二甲双胍或吉非贝齐治疗后，肾脏 CD36 或钠葡萄糖共转运蛋白 2（SGLT2）的表达没有差异。二甲双胍和吉非贝齐可通过 AMPK/PPARα 依赖性途径减轻肥胖状态下 HFD 引起的肾脏损伤。有趣的是，二甲双胍通过调节 AMPK 调节的 SREBP1/FAS 信号通路，在减轻肾脏脂肪毒性方面比吉非贝齐更有效。
