Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Life Sci. 2019 Sep 1;232:116644. doi: 10.1016/j.lfs.2019.116644. Epub 2019 Jul 10.
(5R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation.
Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism.
LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis.
Our results provide a novel application of LLDT-8 in improving NAFLD.
(5R)-5-羟基雷公藤内酯醇（LLDT-8）是一种雷公藤内酯醇类似物，具有出色的抗癌、抗脑缺血损伤和类风湿关节炎能力。在这里，我们通过改善肝脂质积累，在非酒精性脂肪性肝病（NAFLD）小鼠模型中发现了它的保肝作用。
雄性 C57BL/6J 小鼠用高脂肪/高果糖（HFHFr）饮食喂养 29 周，以诱导 NAFLD 的病理现象。然后，将小鼠用 LLDT-8（0.5mg/kg 和 1mg/kg）或载体处理 8 周。最后，检测血清生化指标、肝组织学特征、肝内脂肪酸（FA）谱和相关基因表达，以研究 LLDT-8 对脂质积累的影响及其可能的机制。
LLDT-8 治疗可显著抑制肝损伤，表现为血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）降低，肝气球样变和大泡性脂肪变性减轻。此外，LLDT-8 可下调硬脂酰辅酶 A 去饱和酶 1（SCD1）的表达，进而降低 C16:1/C16:0 和 C18:1/C18:0 的比值，从而抑制脂质合成。LLDT-8 治疗还可上调肝过氧化物酶体增殖物激活受体α（PPARα）、肉碱棕榈酰转移酶 1a（Cpt1a）、过氧化物酶体酰基辅酶 A 氧化酶 1（Acox1）、长链酰基辅酶 A 脱氢酶（Acadl）和中链酰基辅酶 A 脱氢酶（Acadm）的表达水平，这些酶参与脂肪酸氧化（FAO），并显著促进脂肪分解。
我们的结果为 LLDT-8 改善 NAFLD 提供了一种新的应用。
