Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou (510006), China.
Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou (510006), China.
Food Funct. 2023 Nov 27;14(23):10459-10474. doi: 10.1039/d3fo03745b.
Previous studies have found that chitosan oligosaccharide (COST) can alleviate the clinical symptoms in non-alcoholic fatty liver disease (NAFLD) patients. We intend to intervene with different concentrations of COST in mice with NAFLD induced by a high fat diet. The basic effect of COST on NAFLD model mice was observed using physiological and biochemical indexes. 16S rRNA sequencing technology was used to analyze the gut microbiota and further analyze the content of short-chain fatty acids (SCFAs). Western blot and RT-PCR were used to detect the effects of COST on the PI3K/AKT/mTOR signaling pathway in the livers of NAFLD mice. It was found that the COST-high-dose group could reduce the weight of NAFLD mice, improve dyslipidemia, and alleviate liver lesions, and COST has a therapeutic effect on NAFLD mice. 16S rRNA sequencing analysis showed that COST could increase the diversity of the gut microbiota in NAFLD mice. The downregulation of SCFAs in NAFLD mice was reversed. WB and RT-PCR results showed that the PI3K/AKT/mTOR signaling pathway was involved in the development of NAFLD mice. COST improved liver lipid metabolism in NAFLD mice by inhibiting liver DNL. COST could increase the expression of thermogenic protein and UCP1 and PGC-1α genes; the PI3K/AKT/mTOR signaling pathway is inhibited at the protein and gene levels. This study revealed that COST regulates the expression of related inflammatory factors caused by lipid toxicity through the gut microbiota and SCFAs, and improves the liver lipid metabolism of HFD-induced NAFLD mice, laying a foundation for the development of effective and low toxicity drugs for the treatment of NAFLD.
先前的研究发现壳寡糖（COST）可以减轻非酒精性脂肪性肝病（NAFLD）患者的临床症状。我们打算用不同浓度的 COST 干预高脂肪饮食诱导的 NAFLD 小鼠。用生理生化指标观察 COST 对 NAFLD 模型小鼠的基本作用。采用 16S rRNA 测序技术分析肠道微生物群，并进一步分析短链脂肪酸（SCFAs）的含量。Western blot 和 RT-PCR 用于检测 COST 对 NAFLD 小鼠肝脏中 PI3K/AKT/mTOR 信号通路的影响。结果发现 COST-高剂量组可降低 NAFLD 小鼠体重，改善血脂异常，减轻肝损伤，对 NAFLD 小鼠具有治疗作用。16S rRNA 测序分析表明，COST 可增加 NAFLD 小鼠肠道微生物群的多样性。NAFLD 小鼠中 SCFAs 的下调得到逆转。WB 和 RT-PCR 结果表明，PI3K/AKT/mTOR 信号通路参与了 NAFLD 小鼠的发生。COST 通过抑制肝内 DNL 改善 NAFLD 小鼠的肝脂代谢。COST 可增加解偶联蛋白 1（UCP1）和过氧化物酶体增殖物激活受体γ 共激活因子 1α（PGC-1α）基因的表达；在蛋白和基因水平上抑制 PI3K/AKT/mTOR 信号通路。本研究揭示了 COST 通过肠道微生物群和 SCFAs 调节脂质毒性引起的相关炎症因子的表达，改善 HFD 诱导的 NAFLD 小鼠的肝脂代谢，为开发有效、低毒的治疗 NAFLD 药物奠定了基础。
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