脂肪生成
脂肪肝
化学
肝细胞
白蛋白
脂肪酸合酶
脂肪变性
血清白蛋白
生物化学
内科学
内分泌学
药理学
生物
脂肪酸
脂质代谢
医学
疾病
体外
作者
Ni Fan,Jia Zhao,Wei Zhao,Xiuying Zhang,Qingchun Song,Yanting Shen,Ho Cheung Shum,Yu Wang,Jianhui Rong
标识
DOI:10.1016/j.jconrel.2022.04.034
摘要
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with several liver-associated pathologic characteristics such as aberrant lipid accumulation, persistent chronic inflammation and hyperactive endoplasmic reticulum (ER) stress. Plant-derived celastrol (CEL) appeared to be a promising anti-inflammatory and anti-obesity drug but the clinical application was delayed by low oral bioavailability. The present study was designed for developing biodegradable albumin-based nanoparticles to deliver CEL to the liver for treating NAFLD. CEL was entrapped into lactosylated bovine serum albumin (Lac-BSA) by high pressure homogenization to generate CEL-loaded Lac-BSA nanoparticles (CEL-Lac-BSA). CEL-Lac-BSA displayed spherical morphology, narrow size distribution at 158.6 ± 3.4 nm and reasonable drug-loading efficiency at 13.62 ± 0.13%. CEL-Lac-BSA not only showed better hepatocyte uptake and hepatic deposition than free CEL, but also outperformed in reducing lipid deposition, ameliorating liver function and enhancing insulin sensitivity in a mouse model of diet-induced NAFLD. Mechanistic studies indicated that CEL-Lac-BSA more effectively downregulated the mRNA levels of genes for lipogenesis and lipid transporter while upregulated the mRNA levels of lipolysis mediators. Western blot analysis confirmed the outperformance of CEL-Lac-BSA in enhancing the activation of AMP-activated protein kinase (AMPK) and silent information regulation 2 homolog (SIRT1) and the protein levels of fatty acid synthase (FASN) and sterol regulatory element-binding protein-1c (SREBP1c) in NAFLD mice. Taken together, CEL-Lac-BSA showed better potential in the treatment of diet-induced NAFLD. Lactose-coating of albumin-based nanoparticles effectively facilitated the liver-targeting release of hydrophobic drug CEL for ameliorating hepatic steatosis. Therefore, CEL-Lac-BSA may be translated into a potential clinical therapy against obesity and NAFLD.
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