Artrsunate Regulates Lipid Metabolism Through AMPK And PPAR Signaling Pathways

Objective: Artesunate is an important artemisinin derivative.Our previous research found that artesunate also has a role in lowering blood lipids.But the mechanism of its effect on lipid metabolism is not clear.This project intends to explore the mechanism of the effect of artesunate on lipid metabolism.It is useful for providing a theoretical basis for the application of artemisinin derivatives in the diseases related to lipid metabolism.Methods: We induced the serum level of lipids elevated in Syrian golden hamsters by feeding them the high-fat diet,which were treated with different medications.Gas chromatography-time-of-flight mass spectrometry(GC-TOF MS)was used to screen out metabolites with significant changes in the artesunate-treated group compared with the model group.The cell models of lipid accumulation were established in vitro,and q RT-PCR technology was used to verify the gene expression on the pathway,in order to clarify the target genes that artesunate affects about lipid metabolism.Results: The serum biochemical test results of Syrian golden hamsters showed that artesunate can significantly reduce the content of triglyceride(TG),cholesterol(TC)and low-density lipoprotein(LDL-c)in the serum.At the same time,it could increase the level of apo A-I(apolipoprotein-I)without affecting the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST).The results of Gas chromatography-time-of-flight mass spectrometry(GC-TOFMS)showed that the levels of cholesterol(TC),triglycerides(TG),and various long-chain fatty acids in the serum decreased significantly after the treatment of artesunate.The levels of lactic acid,threonine,and lysine were increased,which can promote the oxidation of fatty acids.And the level of acetoacetic acid,an intermediate product of fatty acid oxidation,was increased after the treatment of artesunate.They indicated that artesunate may reduce the content of lipid through the oxidation of fatty acids.Leucine,which can reduce the activity of proteins related to the transport and synthesis of fatty acids,also increased significantly.The content of bile acid related to cholesterol metabolism increased after the intervention of artesunate,suggesting that artesunate can promote the conversion of cholesterol to bile acids,thereby reducing lipid content.In the high-fat model of HepG2 cells induced by free fatty acids(FFA),artesunate can reduce the content of lipids in cells and make the intracellular lipid droplets smaller.The results acquired from q RT-PCR showed that artesunate could down-regulate the mRNA levels of Cide-A and Cide-B related to lipid droplet synthesis.In addition,artesunate can up-regulate the mRNA levels of AMPKα and PPARα/γ,and then up-regulate the mRNA levels of CD36 and CPT-1,while reducing the mRNA levels of SREBP-1c,ACC,SCD1,and FAS.In the high-fat model of RAW264.7 cells induced by cholesterol,the results showed that artesunate can up-regulate the mRNA levels of AMPKαand PPARα/γ,then up-regulate the mRNA levels of CPT-1,LXRα,and APOA1,and reduce the mRNA levels of SREBP-1c.In addition,artesunate indirectly increased the expression levels of ABCA1 and ABCG1.Conclusion: Artesunate significantly reduced the levels of lipids in the serum of hamsters,the accumulation of FFA in HepG2 cells,and the accumulation of cholesterol in RAW264.7 cells.Combining the whole animal metabolomics datas,previous cell transcriptome datas,and the expressions of related genes,it was speculated that artesunate may inhibit the synthesis of fatty acids through the AMPKα/PPARs-SREBP1C-FAS/ACC1/SCD1 signaling pathway.And it could through the AMPKα/PPARs-CD36-CPT-1 signaling pathway to promote the β-oxidation of fatty acids.Furthermore,the signaling pathways of PPARs-LXRα-ABCA1/ABC G1 and PPARs-APOA1 promoted the reverse transport of cholesterol to achieved the effect of lipid reduction.