Characteristics Of Hepatic Fatty Acid Compositions With Nonobese Mice Of Nonalcoholic Fatty Liver Disease And FTZ Intervention

Background:Liver is an important target organ of glycolipid metabolism.Fat accumulation in the liver is accompanied by the changes of fatty acid structure and content.FTZ is a compound Chinese medicine developed under the guidance of traditional Chinese medicine theory.Previous studies have confirmed that the FTZ has the effect in treating diabetes,non-alcoholic fatty liver disease(NAFLD)and regulating the homeostasis of glycolipid metabolism.However,obese mice induced by high-fat diet are generally used as the model of pharmacological studies.Non-obese NAFLD phenotype is not uncommon in metabolic syndrome.To further explore the role of FTZ in the fatty acid composition in the liver of mice with non-obese,the study was carried out in a non-obese fatty liver disease model aP2-nSREBP-1c.Objective:1.To study the glucose and lipid metabolism phenotype and liver fatty acid composition characteristics of aP2-nSREBP-1c mice.2.To study the liver acid composition of C57BL/6J mice,ob/ob mice,db/db mice and aP2-nSREBP-1c mice induced by high fat diet,and to analyze the characteristics of fatty acid composition in the liver of non-alcoholic fatty liver disease under obese and non-obese phenotype.3.To observe the changes of liver fatty acid composition and the therapeutic effect on hepatic ectopic deposition in mice with non-obese fatty liver disease model after FTZ intervention.Methords:1.The aP2-nSREBP-1c model mice were divided into transgenic model group and littermate wild type control group according to genotype.Blood levels of glucose(GLU),total cholesterol(TC),triglyceride(TG),high density liptein cholesterol(HDL-C)and low density liptein cholesterol(LDL-C)were measured;analysis of fatty acid composition in liver tissue;adipose tissue for pathological observation.2.C57BL/6J mice were divided into two groups.The control group was given normal feed,and the model group was induced by high fat diet.After 16 weeks of high fat feeding,the mice were dissected and the fatty acid components of the liver were analyzed by GC-MS.ob/ob,db/db,aP2-nSREBP-1c model mice were divided into transgenic model group and littermate wild-type control group according to genotype.Liver tissues were taken after dissected,and fatty acid components were analyzed by GC-MS.The characteristics of fatty acid composition in liver of non-alcoholic fatty liver disease were analyzed.3.aP2-nSREBP-1c model mice were divided into transgenic model group and littermate wild-type control group according to genotype.After 12 weeks of administration,the mice were dissected and the metabolism of fatty acid components in liver was analyzed by GC-MS.The differential fatty acids were found according to VIP value and P value by PCA analysis with MetaboAnalyst.The pathological conditions of liver tissues were observed by HE staining.RT-PCR was used to detect the expression of elongase of very long chain fatty acids 6(ELOVL6),stearyl coenzyme A desaturase 1(SCD1),adipose triglyceride lipase(ATGL)and peroxisome proliferator-activated receptor alpha(PPARα)genes in liver tissue.Results:1.The white fat of aP2-nSREBP-1c mice was atrophic;the levels of lactic acid,3-hydroxybutyrate,d-galactose,D-allose,and inositol related to glucose metabolism were significantly increased;The content of stearic acid,palmitic acid,oleic acid and 11-octadecenoic acid increases;the content of L-proline and urea increases.Blood biochemical tests showed that GLU,TC,HDL-C,LDL-C and TG were different from the littermate control group;liver C18:0,C16:0,C18:1n9,C22:6n3,C20:4n6,which is the main differential fatty acid component.2.Quantitative analysis of fatty acid components performed on four groups of model mice,and 37 fatty acid components were identified.These fatty acids have different degrees in different metabolic environments,while C18:0,C16:0,C18:1n9c,C16:1,C22:6n3,C18:2n6c,C20:4n6 are the major fatty acid components of the liver.It accounts for a large proportion of total fatty acids,among which C18:0,C18:1n9c,C16:1,C22:6n3,C20:4n6 are related to TG content.In addition,under non-obese NAFLD,the total fatty acids n-3 PUFA,n-6 PUFA decreased and MUFA increased,and the fatty acid ratio C18:1/C18:0,C16:1/C16:0 and n-6/n-3 PUFA increased,which was also the common fatty acid in obese mice.3.FTZ intervention can improve the pathological characteristics of glucose metabolism disorder,cholesterol and triglyceride lipid metabolism in mice with aP2-nSREBP-1c transgenic model.Liver HE staining and oil red O staining showed that the structure of hepatocytes after FTZ intervention was normal compared with the model group.In the nuclear population,the lipid droplet vacuoles were significantly reduced.The fatty acid composition showed that FTZ can significantly reduce C18:1n9c,increase C18:0,C22:6n3,C20:4n6 content;change NAFLD characteristics fatty acid composition MUFA,PUFA,C18: 1/C18:0,C16:1/C16:0.The results of PCR showed that FTZ could decrease the expression of ELOVL6 and SCD1 mRNA in liver of model mice,increase the expression of ATGL and PPARα mRNA,and finally alleviate the process of liver fat ectopic deposition.Conclusion:The experimental results show that FTZ intervention can improve the disorder of glucose and lipid metabolism in aP2-nSREBP-1c non-obese NAFLD mice;reduce the heterotopic fat ectopic deposition and improve the disorder of fatty acid metabolism in liver.On the one hand,the mechanism of FTZ is related to the promotion of fatty acid oxidation,thereby reducing the accumulation of fatty acid intermediates in the liver;on the other hand,it is related to the promotion of lipolysis and the reduction of abnormal accumulation of triglycerides.