Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky.
Am J Physiol Endocrinol Metab. 2021 Mar 1;320(3):E609-E618. doi: 10.1152/ajpendo.00135.2020. Epub 2021 Jan 18.
Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARγ) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk. Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARγ-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.
肥胖与肝脂质代谢改变有关。我们之前发现，前胰蛋白酶受体（PRR）可能是肝脂肪变性的一个潜在贡献者。因此，我们旨在确定 PRR 及其可溶性形式 sPRR 对脂质稳态的相对贡献。用甲状腺素结合球蛋白启动子驱动的腺相关病毒处理 PRR 基因敲除（KO）的雄性小鼠，以在肝脏中删除 PRR [肝 PRR 敲除（KO）小鼠]。肝脏中 PRR 的缺失并没有改变体重，但增加了肝脏重量。肝脏中 PRR 的缺失降低了过氧化物酶体增殖物激活受体γ（PPARγ）和甘油三酯水平，但肝 PRR KO 小鼠的血浆胆固醇水平较高，而肝低密度脂蛋白受体（LDLR）和分选蛋白 1（SORT1）蛋白水平较低。令人惊讶的是，肝 PRR 的缺失增加了肝脏胆固醇，并上调了肝固醇调节元件结合蛋白 2（SREBP2）和 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMG CoA-R）基因。此外，肝 PRR KO 小鼠的血浆 sPRR 水平明显高于对照组。HepG2 细胞的体外研究表明，sPRR 处理上调了 SREBP2，表明 sPRR 可能有助于肝脏胆固醇的生物合成。有趣的是，肝 PRR KO 小鼠的脂肪组织中 PRR、总裂解和非裂解 sPRR 含量、furin 和位点 1 蛋白酶（S1P）升高，表明脂肪组织可能有助于循环 sPRR 池。总的来说，这项工作支持了以前的工作，并开辟了一个新的研究领域，涉及 sPRR 在脂质代谢和脂肪组织-肝脏对话中的功能。肝 PRR 及其可溶性形式 sPRR 有助于甘油三酯和胆固醇稳态以及肝炎症。通过 PRR-PPARγ 依赖性机制，肝 PRR 的缺失降低了甘油三酯水平，但通过 sPRR 介导的 SREBP-2 上调增加了肝胆固醇合成。我们的研究强调了涉及胆固醇和 sPRR 的肝脏和脂肪组织之间的新对话范式。
