Excessive accumulation of cholesterol in the arteries drives atherosclerosis development. It is believed that biliary cholesterol secretion is crucial for eliminating excess cholesterol from the body via reverse cholesterol transport. In the current study, we wanted to determine the impact of reduced biliary cholesterol secretion on atherosclerosis development in mice. Decreased biliary cholesterol secretion was achieved by hepatic over-expression of human NPC1L1 (L1Tg mice) combined with knockdown of hepatic ABCG5/G8 function using an ABCG8 antisense oligonucleotide (ASO). LDLR-/- and LDLR-/-/L1Tg mice received either control or ABCG8 ASO and were fed a high fat (42% Kcal)/low cholesterol diet (0.015% wt/wt) for 20 weeks. As expected, L1Tg mice and mice with hepatic ABCG8 knockdown had an >70% reduction in biliary cholesterol. The dramatic decrease in biliary cholesterol did not increase plasma cholesterol, and in fact mice with hepatic ABCG8 knockdown had reduced VLDL cholesterol. Even more surprising, aortic atherosclerosis was significantly decreased in mice with compromised biliary cholesterol secretion. LDLR-/-/L1Tg treated with ABCG8 ASO had a >90% reduction in biliary cholesterol yet had ~70% less atherosclerosis compared to LDLR-/- controls. Moreover, reducing biliary cholesterol had no impact on macrophage reverse cholesterol transport, fecal excretion of neutral sterol, and hepatic expression of genes involved in cholesterol synthesis (HMG CoA reductase/synthase) and HDL metabolism (ABCA1 and SR-BI). These results indicate that atherosclerosis development can be decreased by shunting cholesterol away from biliary secretion and potentially towards trans-intestinal cholesterol excretion or bile acid synthesis.
Hepatic expression of ABC transporters G5 and G8 does not correlate with biliary cholesterol secretion in liver transplant patients
