The Discovery And Mechanism Study Of SREBP Modulator

Ectopic hepatic lipid deposition is a major point in the development of insulin resistance, nonalcoholic fatty liver (NAFLD), hyperlipidemia, atherosclerosis and other related complications induced by obesity. In liver, SREBP (sterol regulatory element binding protein) is a family of key nuclear transcription factors, which directly activate more than30genes dedicated to synthesis and uptake of fatty acid, triglyceride, cholesterol. SREBP plays an important role in regulating lipid homeostasis. A lot of researches had shown that SREBP was involved in composition of insulin signal pathway, at the same time, patients diagnosed with diabetes, hyperlipidemia, fatty liver disease were characterized by overexpression of SREBP. Targeted SREBP will become a new and effective strategy for treatment related metabolic diseases.Based on luciferase reporter assay containing SRE component, we found a novel small molecule ZJ001which specifically inhibited transcriptional activity of SREBP. ZJ001inhibited the luciferase activity driven by SRE-containing promoter in a dose-dependent manner, and the inhibitory effect was abolished by SRE mutagenesis (C/A). ZJ001down-regulated the mRNA of SREBP and their target genes, and also inhibited de novo cholesterol and fatty acids in vitro.The net increase in body weight of obese mice was less than the control group after long-term treatment of ZJ001. Similarly, white adipose tissue weight was significantly reduced. Plasma cholesterol and LDL-c/HDL-c ratio was remarkably decreased, which may lower the risk of atherosclerosis. After chronic treatment of ZJ001, obese mice liver weight was reduced, and triglyceride and cholesterol levels in liver were also decreased, suggesting ZJ001, to some extent, had potential to improve fatty liver. Furthermore, ZJ001also enhanced the capacity of the glucose tolerance in obese mice. ZJ001downregulated SREBP and their target genes involved in lipid synthesis in liver, as well as in hepatic cells. Meanwhile, genes involved in lipid oxidation were not altered, prompting ZJ001lowered lipid mainly by inhibiting lipid synthesis. The lipid-lowering effect of ZJ001might result from suppression of mTORCl which regulates SREBP-lc transcription. ZJOO1blocked mTOR activity through activation of AMPK and subsequent phosphorylation of Raptor. This was also evidenced by enhanced phosphorylation of AMPK and its downstream ACC and decrease in the phosphorylation of mTOR in vivo. ZJ001probably stimulated AMPK by uncoupling of mitochondria electron respiration chain which may decrease intracellular ATP content.In conclusion, we concluded that the lipid-lowering effect of ZJ001was possibly mediated by AMPK/mTORCl/SREBP-lc pathway:ZJ001stimulated AMPK activity, thereby inhibited mTORC1-mediated SREBP-1c transcription, hence reduced transcriptional expression of crucial genes involved in lipogenesis. ZJ001showed a multitude of beneficial effects in vivo, proving that SREBP could be a potential therapeutic target to treat obesity and obesity-induced comorbidities. ZJ001could serve as a promising therapeutic option for obesity and obesity-induced comorbidities for pharmacological control of metabolic diseases.