Synergic hypocholesterolemic effect of n-3 polyunsaturated fatty acids and estrogen by modulation of hepatic cholesterol metabolism

Abstract

N-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as well as estrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the synergic effect of n-3 PUFA supplementation and estrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0%, 1% or 2% n-3 PUFAs (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomized at week 8, and after one week recovery, rats were injected with 17β-estradiol-3-benzoate (E2) or corn oil for the last 3 weeks. Supplementation of n-3 PUFAs and E2 injection were significantly increased hepatic expression of phosphorylated adenosine monophosphate activated protein kinase (p-AMPK)/ AMPK ratio, and decreased sterol regulatory element-binding protein-2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Supplementation of n-3 PUFAs increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1), and sterol 27-hydroxylase (CYP27A1), but E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of estrogen receptor- α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolemic effects by down-regulation of hepatic cholesterol synthesis by both n-3 PUFAs and estrogen, and up-regulation of bile acid synthesis by n-3 PUFAs in ovariectomized rats.