Synergistic Cholesterol-Lowering Effects of N-3 PUFA and Probiotics via Modulation of Cholesterol Synthesis and Clearance in Depressed Rats Exposed to Chronic Mild Stress

Objectives: We hypothesized that n-3 polyunsaturated fatty acids (PUFA) combined with live and dead probiotics synergistically improves depression-induced dyslipidemia by modulating the regulation of cholesterol synthesis and clearance. Methods: Rats are randomly divided into seven groups (n=8/group): non-chronic mild stress (CMS) with n-6 PUFA, CMS with n-3 PUFA, n-6 PUFA, live probiotics, dead probiotics, n-3 PUFA and live probiotics, and n-3 PUFA and dead probiotics. Diets of n-6 and n-3 PUFA, and oral supplementation of live and dead probiotics were provided for 12 weeks, and CMS was performed for the last 5 weeks. Results: N-3 PUFA and probiotics significantly decreased serum and hepatic levels of total cholesterol and triglycerides, serum levels of low-density lipoprotein cholesterol (LDL-C), and increased serum levels of high-density lipoprotein cholesterol. N-3 PUFA and probiotics reduced cholesterol synthesis by synergistically lowering the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and sterol regulatory element-binding protein-2 in the liver and ileum. N-3 PUFA and probiotics synergistically increased LDL-C clearance via LDL-C reuptake by reducing the expression of proprotein convertase subtilisin/kexin type 9 in the liver and ileum and via regulation of bile acid (BA) metabolism. Synthesis of BA was increased by hepatic gene expression of cholesterol 7α-hydroxylase and sterol 27-hydroxylase, enterohepatic circulation of BA was enhanced by upregulating sodium/bile acid cotransporter, and bile salt export pump, and BA reabsorption was inhibited by decreased ileal gene expression of apical sodium-dependent bile acid transporter. There was no significant difference in cholesterol metabolism between the live and dead probiotics. Conclusions: In conclusion, n-3 PUFA and probiotics synergistically improved depression-induced dyslipidemia by modulating cholesterol synthesis and clearance. Funding Sources: This study was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) project of the National Research Foundation of Korea Grant, and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT).