Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state

Abstract

Procyanidin B2, a naturally occurring phenolic compound, has been reported to exert multiple beneficial functions. However, the effect of procyanidin B2 on free fatty acids (FFAs)-induced hepatic steatosis remains obscure. The present study is therefore aimed to elucidate the protective effect of procyanidin B2 against hepatic steatosis and its underlying mechanism. Herein, we reported that procyanidin B2 attenuated FFAs-induced lipid accumulation and its associated oxidative stress by scavenging excessive ROS and superoxide anion radicals, blocking loss of mitochondrial membrane potential, restoring glutathione content, and increasing activity of antioxidant enzymes (GPx, SOD and CAT) in hepatocytes. Procyanidin B2 mechanistically promoted lipid degradation via modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathway. Molecular docking analysis indicated a possible ligand-binding position of procyanidin B2 with TFEB. In addition, administration of procyanidin B2 resulted in a significant reduction of hepatic fat accumulation in high-fat diet (HFD)-induced obese mice, and also ameliorated HFD-induced metabolic abnormalities, including hyperlipidemia and hyperglycemia. It was confirmed that procyanidin B2 prevented HFD-induced hepatic fat accumulation through down-regulating lipogenesis-related gene expressions (PPARγ, C/EBPα and SREBP-1c), inhibiting pro-inflammatory cytokines production (IL-6 and TNF-α) and increasing antioxidant enzymes activity (GPx, SOD and CAT). Moreover, hepatic fatty acids analysis indicated that procyanidin B2 caused a significant increase in the levels of palmitic acid, oleic acid and linoleic acid. Intriguingly, procyanidin B2 restored the decreased nuclear TFEB expression in HFD-induced liver steatosis and up-regulated its target genes involved in lysosomal pathway (Lamp1, Mcoln, Uvrag), which suggested a previously unrecognized mechanism of procyanidin B2 on ameliorating HFD-induced hepatic steatosis. Taken together, our results demonstrated that procyanidin B2 attenuated FFAs-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state, which had important implications that modulation of TFEB might be a potential therapeutic strategy for hepatic steatosis and procyanidin B2 could represent a promising novel agent in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD).

原花青素B2是一种天然酚类化合物，具有多种有益功能。然而，原花青素B2对游离脂肪酸(FFAs)诱导的肝脂肪变性的影响尚不清楚。本研究旨在阐明原花青素B2对肝脂肪变性的保护作用及其机制。本研究发现，原花青素B2可通过清除肝细胞中过多的ROS和超氧阴离子自由基，阻断线粒体膜电位的损失，恢复谷胱甘肽含量，提高抗氧化酶(GPx、SOD和CAT)活性，从而降低脂质积聚及其相关的氧化应激。原花青素B2通过调节转录因子EB (TFEB)促进脂质降解，TFEB是溶酶体途径的主要调控因子。分子对接分析表明，原花青素B2与TFEB可能存在配体结合位置。此外，原花青素B2可显著降低高脂饮食(HFD)诱导的肥胖小鼠的肝脏脂肪堆积，改善HFD诱导的高脂血症、高血糖等代谢异常。研究证实，原花青素B2通过下调脂肪生成相关基因(PPARγ、C/EBPα和SREBP-1c)的表达，抑制促炎细胞因子(IL-6和TNF-α)的产生，并提高抗氧化酶(GPx、SOD和CAT)活性，从而抑制高脂脂肪诱导的肝脏脂肪积累。此外，肝脂肪酸分析表明，原花青素B2导致软脂酸、油酸和亚油酸水平显著升高。有趣的是，原花青素B2恢复了hfd诱导的肝脂肪变性中TFEB核表达的减少，并上调了其参与溶酶体途径的靶基因(Lamp1, Mcoln, Uvrag)，这表明原花青素B2改善hfd诱导的肝脂肪变性的机制尚未被认识。综上所述，我们的研究结果表明，原花青素B2通过调节tfeb介导的溶酶体途径和氧化还原状态来减弱ffas诱导的肝脏脂肪变性，原花青素B2可能是一种预防和治疗非酒精性脂肪性肝病(NAFLD)的新型药物。

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https://www.sciencedirect.com/science/article/abs/pii/S0891584918314394