A new framework for reverse cholesterol transport: non-biliary contributions to reverse cholesterol transport

Abstract

Reduction of low-density lipoprotein-cholesterol through statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Major efforts are now focused on therapies that augment high-density lipoprotein (HDL)-mediated reverse cholesterol transport (RCT), and ultimately increase the fecal disposal of cholesterol. The process of RCT has long been thought to simply involve HDL-mediated delivery of peripheral cholesterol to the liver for biliary excretion out of the body. However, recent studies have revealed a novel pathway for RCT that does not rely on biliary secretion. This non-biliary pathway rather involves the direct excretion of cholesterol by the proximal small intestine. Compared to RCT therapies that augment biliary sterol loss, modulation of non-biliary fecal sterol loss through the intestine is a much more attractive therapeutic strategy, given that excessive biliary cholesterol secretion can promote gallstone formation. However, we are at an early stage in understanding the molecular mechanisms regulating the non-biliary pathway for RCT, and much additional work is required in order to effectively target this pathway for CHD prevention. The purpose of this review is to discuss our current understanding of biliary and non-biliary contributions to RCT with particular emphasis on the possibility of targeting the intestine as an inducible cholesterol secretory organ.

Figure 1

Biliary and non-biliary fecal cholesterol excretion. In this proposed model, cholesterol is effluxed from peripheral cells onto high-density lipoprotein (HDL) and then delivered to the liver or small intestine via HDL or very low density lipoprotein (VLDL)/low-density lipoprotein (LDL) following cholesterol ester transfer protein-mediated transfer. The cholesterol internalized or de novo synthesized by the liver is secreted into bile through the action of ABCG5/G8 and subsequently excreted in the feces. Alternatively, the liver secretes the cholesterol in apoB-containing lipoproteins or HDL containing apoAI or apoE, which are specifically targeted to the small intestine. After being internalized by scavenger receptor, class B, type I (SR-BI), LDL receptor (LDLR), or another lipoprotein receptor system, the cholesterol is trafficked across the enterocytes to the brush border membrane and effluxed into the intestinal lumen by ABCG5/G8 or a currently unidentified cholesterol transporter.