β-estradiol adjusts intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia

Decreases in estrogen secretion and estrogen receptor function lead to an increase in the incidence of dyslipidemia and cardiovascular disease (CVD) in postmenopausal women. We previously reported that β-estradiol has a significant regulatory effect on lipids in ApoE−/− mice with bilateral ovariectomy. In the present study, we investigated how β-estradiol regulates intestinal function via estrogen receptors to alleviate postmenopausal dyslipidemia. Ovariectomized ApoE−/− mice were treated with β-estradiol for 90 days, and we found that β-estradiol reduced TC, TG, LDL-c, IL-1β and IL-18 levels in serum and decreased lipid accumulation in the liver. β-estradiol reduced injury and inflammation in the jejunum in ovariectomized mice, and promoted the expression of tight junction-related proteins. Moreover, β-estradiol increased ERα, ERβ, GPR30 and ABCG5 protein expression, and decreased the levels of NPC1L1 and SR-B1 in the jejunum of ovariectomized mice. In Caco-2 cells incubated with cholesterol, β-estradiol up-regulated PI3K/AKT signaling, reduced cholesterol accumulation, suppressed inflammatory signaling, and increased the expression of tight junction-related proteins. ERβ or GPR30 inhibition decreased the protective effect of β-estradiol on cholesterol accumulation, tight junctions, and inflammation in cholesterol incubated Caco-2 cells, while silencing both ERβ and GPR30 completely eliminated the protective effect of β-estradiol. PI3K/AKT inhibition abolished the protective effect of β-estradiol on cholesterol accumulation, tight junction-related protein expression, and inflammation, but had no influence on ERα, ERβ or GPR30 expression in cholesterol incubated Caco-2 cells. Our results provide evidence that β-estradiol regulates intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia.