Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
Mol Ther. 2019 Oct 2;27(10):1848-1862. doi: 10.1016/j.ymthe.2019.06.017. Epub 2019 Jul 12.
Non-alcoholic steatosis and non-alcoholic steatohepatitis (NASH) are liver pathologies characterized by severe metabolic alterations due to fat accumulation that lead to liver damage, inflammation, and fibrosis. We demonstrate that the voltage-dependent anion channel 1 (VDAC1)-based peptide R-Tf-D-LP4 arrested steatosis and NASH progression, as produced by a high-fat diet (HFD-32) in a mouse model, and reversed liver pathology to a normal-like state. VDAC1, a multi-functional mitochondrial protein, regulates cellular metabolic and energetic functions and apoptosis and interacts with many proteins. R-Tf-D-LP4 treatment eliminated hepatocyte ballooning degeneration, inflammation, and liver fibrosis associated with steatosis, NASH, and hepatocarcinoma, and it restored liver pathology-associated enzyme and glucose levels. Peptide treatment affected carbohydrate and lipid metabolism, increasing the expression of enzymes and factors associated with fatty acid transport to mitochondria, enhancing β-oxidation and thermogenic processes, yet decreasing the expression of enzymes and regulators of fatty acid synthesis. The VDAC1-based peptide thus offers a promising therapeutic approach for steatosis and NASH.
非酒精性脂肪性肝病和非酒精性脂肪性肝炎（NASH）是由于脂肪堆积导致严重代谢改变而引起的肝脏病变，可导致肝损伤、炎症和纤维化。我们证明，基于电压依赖性阴离子通道 1（VDAC1）的肽 R-Tf-D-LP4 可阻止高脂肪饮食（HFD-32）诱导的小鼠模型中的脂肪变性和 NASH 进展，并将肝病理逆转至正常状态。VDAC1 是一种多功能线粒体蛋白，可调节细胞代谢和能量功能以及细胞凋亡，并与许多蛋白质相互作用。R-Tf-D-LP4 治疗可消除与脂肪变性、NASH 和肝癌相关的肝细胞气球样变性、炎症和肝纤维化，并恢复与肝病理相关的酶和葡萄糖水平。肽治疗影响碳水化合物和脂质代谢，增加与脂肪酸向线粒体转运相关的酶和因子的表达，增强β-氧化和生热过程，同时降低脂肪酸合成的酶和调节剂的表达。因此，基于 VDAC1 的肽为脂肪变性和 NASH 提供了一种有前途的治疗方法。
