College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, PR China.
Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310013, PR China.
Int J Biochem Cell Biol. 2021 Oct;139:106067. doi: 10.1016/j.biocel.2021.106067. Epub 2021 Aug 20.
Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, ranging from benign steatosis to severe non-alcoholic steatohepatitis. Recently, it has been found that lipophagy plays a pivotal role in lipid turnover, which can alleviate NAFLD in hepatocytes. In this study, we found that a highly sulfated glucuronomannan hexamer G6S1 has the ability to enhance lipophagy. When treated with G6S1, the number and the size of lipid droplet (LD) decreased significantly on hepatocytes AML12 cells. Western blot results showed that the expressions of the lipolysis-related proteins increased, while the expressions of proteins that is responsible for lipid transportation and synthesis exhibited no significant change. Immunofluorescence assay and electron microscopy results showed an increase of autophagy related protein expression level and lysosome number in hepatocytes treated with G6S1, suggesting that G6S1 could also promote lipophagy. A significant increase of peroxisome proliferator-activated receptor alpha (PPARα) expression level was detected in G6S1 treated cells, suggesting that G6S1 may promote autophagy via enhancing the expression of PPARα. In addition, these effects could be inhibited after treatment with autophagy inhibitor 3-methyladenine (3-MA) and PPARα inhibitor MK-886. These findings indicate that G6S1 can promote lipophagy via enhanced PPARα expression and can result in a slowdown of lipids accumulation.
非酒精性脂肪性肝病（NAFLD）被认为是代谢综合征的肝脏表现，其范围从良性脂肪变性到严重的非酒精性脂肪性肝炎。最近发现，脂噬作用在脂质周转中起着关键作用，可以减轻肝细胞中的 NAFLD。在这项研究中，我们发现高度硫酸化的葡甘露聚糖六聚体 G6S1 具有增强脂噬作用的能力。用 G6S1 处理后，AML12 细胞中肝细胞的脂滴（LD）数量和大小明显减少。Western blot 结果表明，脂解相关蛋白的表达增加，而负责脂质转运和合成的蛋白表达没有明显变化。免疫荧光和电子显微镜结果表明，G6S1 处理的肝细胞中自噬相关蛋白表达水平和溶酶体数量增加，表明 G6S1 还可以促进脂噬作用。在 G6S1 处理的细胞中检测到过氧化物酶体增殖物激活受体α（PPARα）表达水平的显著增加，表明 G6S1 可能通过增强 PPARα 的表达来促进自噬。此外，用自噬抑制剂 3-甲基腺嘌呤（3-MA）和 PPARα 抑制剂 MK-886 处理后，这些作用可以被抑制。这些发现表明，G6S1 可以通过增强 PPARα 表达来促进脂噬作用，并导致脂质积累减慢。
