Reciprocal regulation of cholesterol excretion in apolipoprotein E-null mice by angiotensin II type 1 and type 2 receptor deficiency

AimsThe effects of AT1 and AT2 receptor deficiency on the intake and excretion of cholesterol were examined using atherosclerotic apolipoprotein E-null (ApoEKO) mice.Main methodsApoEKO, AT1a/ApoEKO and AT2/ApoEKO mice received a high-cholesterol diet (HCD: 1.25% cholesterol) for 10 days before sampling.Key findingsPlasma total cholesterol level was lower in AT1a/ApoEKO mice and higher in AT2/ApoEKO mice than in ApoEKO mice with a high cholesterol intake. In these mice, cholesterol content in feces was higher in AT1a/ApoEKO mice and lower in AT2/ApoEKO mice than in ApoEKO mice. Moreover, cholesterol content in bile tended to be higher in AT1a/ApoEKO mice and lower in AT2/ApoEKO mice than in ApoEKO mice, while a significant difference was observed only between AT1a/ApoEKO and AT2/ApoEKO mice. Cholesterol content and expression of HMG-CoA reductase and LDL receptor in liver were not different among the groups. Similar but weaker changes were also observed with a normal standard diet. Treatment with an AT1 receptor blocker, irbesartan, increased cholesterol content in bile and tended to increase cholesterol excretion into feces in ApoEKO mice with HCD.SignificanceThese results suggest that AT1 and AT2 receptor stimulation was involved in the regulation of cholesterol excretion into bile and feces, and that the regulation acted reciprocally in a cholesterol overload condition with HCD.