Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA.
Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA.
Biomolecules. 2023 Jan 10;13(1):142. doi: 10.3390/biom13010142.
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD.
非酒精性脂肪性肝病（NAFLD）包括一系列与糖尿病、肥胖和代谢综合征直接相关的肝损伤。最近已经证明，（前）肾素受体（PRR）在葡萄糖和脂质代谢中发挥作用。在这里，我们检验了 PRR 调节饮食诱导的肝脂肪变性和纤维化发展的假说。C57Bl/6J 小鼠用高脂肪饮食（HFD）或含有匹配热量的正常脂肪饮食（NFD）喂养 6 周。用 8 周的蛋氨酸胆碱缺乏（MCD）饮食诱导纤维化。饮食治疗 2 周后，给小鼠皮下植入持续释放含有 PRR 肽拮抗剂 PRO20 或乱序肽的渗透泵 4 或 6 周。与 NFD 喂养的小鼠相比，用 6 周 HFD 喂养的小鼠肝脏脂质积累增加，肝甘油三酯含量增加。重要的是，PRO20 治疗减少了 HFD 喂养的小鼠的肝脂质积累，而不影响体重或血糖。此外，PRR 拮抗作用减弱了 HFD 诱导的脂肪变性，特别是微泡性脂肪变性。在 MCD 饮食模型中，与对照组相比，PRO20 治疗组的胶原面积百分比降低。与对照组相比，PRO20 治疗还显著降低了 MCD 喂养小鼠的肝丙氨酸氨基转移酶水平，这是肝损伤的一个指标。在机制上，我们发现 PRR 拮抗作用阻止了 HFD 诱导的肝甘油三酯合成基因 PPARγ 和甘油-3-磷酸酰基转移酶 3 的表达增加。总之，我们的研究结果表明 PRR 参与了肝脏甘油三酯的合成，并表明 PRR 拮抗治疗非酒精性脂肪性肝病肝脂肪变性和纤维化的治疗潜力。
