The Activity And Molecular Mechanism Of 3,4-Dihydroxyphenylacetic Acid Regulating Glucose And Lipid Metabolism Imbalance

Imbalance of glucose and lipid metabolism is considered to be a major factor in inducing chronic diseases such as obesity,type 2 diabetes,and cardiovascular diseases.Imbalance of glucose and lipid metabolism is a serious risk to human health,which not only causes economic burden,but also leads to the decline of people’s quality of life and life expectancy.Dietary polyphenols with the biological activities of reducing weight and lowering blood sugar levels have attracted extensive attention in recent years.Quercetin and its glycosides,one of the natural polyphenolic flavonoids,have anti-obesity and anti-diabetic effects.However,it is difficult to exert its biological activity directly in organisms due to its low bioavailability in vivo.Previous studies have revealed that its metabolite 3,4-dihydroxyphenylacetic acid may be the material basis for its regulation of glucose and lipid metabolism in vivo.The current research on the role of 3,4-dihydroxyphenylacetic acid in regulating glucose and lipid metabolism is mainly concentrated on in vitro studies.However,the biological activity and mechanism of 3,4-dihydroxyphenylacetic acid in regulating glucose and lipid metabolism in vivo has not been fully studied.In this paper,we used a high-fat diet-induced glucose and lipid metabolic imbalance C57BL/6 mice model to investigate the regulatory effect of 3,4-dihydroxyphenylacetic acid on glucose and lipid metabolic imbalance and to elucidate the molecular mechanism of its regulation of glucose and lipid metabolic imbalance.The main results were shown as follows:(1)Effect of 3,4-dihydroxyphenylacetic Acid on Regulating Glucose and Lipid Metabolism Disorder in High-Fat Diet Fed miceSeventy male C57BL/6 mice were randomly divided into five group: normal control group,3,4-dihydroxyphenylacetic acid control high-dose group,high-fat diet control group,and low-and high-dose 3,4-dihydroxyphenylacetic acid groups(high-fat diet+0.05% and0.1% 3,4-dihydroxyphenylacetic acid).After 10 weeks,the basic physiological and biochemical indexes of each group of mice were determined.3,4-Dihydroxyphenylacetic acid significantly reduced the body weight gain,Lee’s index,the perirenal fat and epididymal fat coefficients,the serum levels of triglyceride,total cholesterol,low-density lipoprotein cholesterol,lipid deposition in hepatocytes and adipocytes,and improved glucose tolerance in mice with high-fat diet induced glucose and lipid metabolism disorders.3,4-Dihydroxyphenylacetic acid had the biological activity of regulating the disorder of glucose and lipid metabolism in obese mice.(2)Effects of 3,4-dihydroxyphenylacetic Acid on Intestinal Microflora of Mice with High Fat Diet16S rRNA technology was used to explore the regulatory effect of 3,4-dihydroxyphenylacetic acid on intestinal microflora of high-fat fed mice.The results showed that 3,4-dihydroxyphenylacetic acid significantly increased the diversity of intestinal microflora in high-fat diet fed mice.3,4-Dihydroxyphenylacetic acid significantly reduced the ratio of Firmicutes to Bacteroides and decreased the relative abundance of Lachnospiraceae,Oscillospiraceae,Ruminococcaceae,Anaerovoracaceae,and Eubacterium＿nodatum＿group in high-fat diet fed mice.3,4-Dihydroxyphenylacetic acid significantly improved the abundance of Lactobacillaceae,Akkermansiaceae,Lactobacillus,Parabacteroides,and Akkermansia in high-fat diet fed mice.Spearman analysis showed that there was a potential relationship between intestinal microflora and the activity of 3,4-dihydroxyphenylacetic acid in regulating imbalance of glucose and lipid metabolism.Those results suggested that 3,4-dihydroxyphenylacetic acid could regulate the biological activity of glucose and lipid metabolism imbalance by regulating the structure and composition of intestinal microflora.(3)Molecular Mechanism of 3,4-dihydroxyphenylacetic Acid on Glucose and Lipid Metabolism Imbalance in High-Fat Diet Fed miceThe molecular mechanism of 3,4-dihydroxyphenylacetic acid on regulating glucose and lipid metabolism imbalance was analyzed by RNA-seq sequencing technique.3,4-Dihydroxyphenylacetic acid caused significant changes in the expression of liver tissue genes in high-fat diet fed mice.3,4-Dihydroxyphenylacetic acid had a different gene compared with HFD group.GO functional enrichment analysis showed that 3,4-dihydroxyphenylacetic acid could significantly regulate the biological processes related to glucose and lipid metabolism.Subsequently,KEGG enrichment analysis showed that 3,4-dihydroxyphenylacetic acid could improve the imbalance of glucose and lipid metabolism in high-fat diet fed mice by regulating metabolism of xenobiotics by cytochrome P450,drug metabolism cytochrome P450,circadian rhythm,and PI3K-AKT signaling pathway related to glucose and lipid metabolism.Analysis of key genes in pathways related to glucose and lipid metabolism revealed that 3,4-dihydroxyphenylacetic acid could inhibit lipogenesis,prevent oxidative stress,protect the liver,improve glucose metabolism,and decrease lipid storage by upregulating the expression of Gstm3,Gstm2,Cry1,Arntl,Ppargc1 a,and Cyp7a1 genes and suppressing the expression of Cidea and Ldha-ps2 genes in the liver of mice fed a high-fat diet.3,4-Dihydroxyphenylacetic acid regulated the imbalance of glucose and lipid metabolism in high-fat diet fed mice.