Celastrol-loaded lactosylated albumin nanoparticles attenuate hepatic steatosis in non-alcoholic fatty liver disease

Ni Fan; Jia Zhao; Wei Zhao; Xiuying Zhang; Qingchun Song; Yanting Shen; Ho Cheung Shum; Yu Wang; Jianhui Rong

doi:10.1016/j.jconrel.2022.04.034

Celastrol-loaded lactosylated albumin nanoparticles attenuate hepatic steatosis in non-alcoholic fatty liver disease

J Control Release. 2022 Jul:347:44-54. doi: 10.1016/j.jconrel.2022.04.034. Epub 2022 May 4.

Authors

Ni Fan¹, Jia Zhao¹, Wei Zhao¹, Xiuying Zhang¹, Qingchun Song², Yanting Shen², Ho Cheung Shum², Yu Wang³, Jianhui Rong⁴

Affiliations

¹ School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
² Department of Mechanical Engineering, The University of Hong Kong, Hong Kong, China.
³ Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
⁴ School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China. Electronic address: jrong@hku.hk.

PMID: 35483638
DOI: 10.1016/j.jconrel.2022.04.034

Abstract

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.

Keywords: Celastrol; Drug delivery; Lactosylated BSA nanoparticles; Non-alcoholic fatty liver disease; Obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diet, High-Fat
Lipid Metabolism
Lipids / therapeutic use
Liver / metabolism
Mice
Mice, Inbred C57BL
Nanoparticles* / chemistry
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism
Pentacyclic Triterpenes
RNA, Messenger / metabolism

Substances

Lipids
Pentacyclic Triterpenes
RNA, Messenger
celastrol