Reverse Cholesterol Transport Does Not Rely on Biliary Sterol Secretion

A recent paper challenged the accepted dogma that excretion of cholesterol (reverse cholesterol transport, or RCT) is dependent on a pathway involving HDL (high-density lipoproteins), the liver, and bile (the hepatic-biliary pathway).

Reverse cholesterol transport is typically described as the process by which peripheral cholesterol is returned to the liver via high-density lipoproteins (HDLs) for secretion into bile and excretion through the feces. In the context of atherosclerosis, RCT is thought to involve HDL-mediated removal of cholesterol from the arterial wall, specifically from cholesterol-laden macrophages. In this view of macrophage RCT, HDL-mediated delivery of peripheral cholesterol to the liver directly promotes biliary and fecal excretion. If this model is correct, then plasma HDL levels should accurately predict both biliary sterol secretion and fecal sterol loss. However, in mice with extremely low HDL levels, biliary and fecal sterol loss is normal. In addition, biliary sterol levels do not accurately predict fecal sterol loss in several mouse models of altered hepatic cholesterol metabolism.

Investigators at Wake Forest University (Winston-Salem, NC, USA) developed several model systems for studying alternative RCT mechanisms. They created both genetic and surgical models of biliary cholesterol insufficiency. To inhibit genetically biliary cholesterol secretion, they genetically engineered a line of mice in which Niemann-Pick C1-Like 1 (NPC1L1) protein was overexpressed in the liver. Compared to controls, these mice exhibited a greater than 90% decrease in biliary cholesterol secretion, yet mass fecal sterol loss and macrophage RCT were normal. To inhibit surgically biliary emptying into the intestine, they established an acute biliary diversion model.

Results published in the July 4, 2010, issue of the journal Cell Metabolism revealed that macrophage RCT persisted in mice surgically or genetically lacking the ability to secrete bile into the intestine. These findings confirmed that mass fecal sterol loss and macrophage RCT could proceed in the absence of biliary sterol secretion, challenging the obligate role of bile in RCT.

The authors concluded by stating, "The classic view of reverse cholesterol transport involved the delivery of peripheral cholesterol via HDL to the liver for secretion into bile. In parallel, we believe that the liver also plays a gatekeeper role for nonbiliary fecal sterol loss by repackaging peripheral cholesterol into nascent plasma lipoproteins that are destined for subsequent intestinal delivery.”

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