Rethinking reverse cholesterol transport

The protective role of HDL, the so-called "good cholesterol," has been attributed to its ability to transport cholesterol to the liver, where it can be incorporated into the bile and eventually excreted. Two players in this pathway have received particular attention: One, the phospholipid/cholesterol transporter ABCA1, is required for the synthesis of HDL, as seen in humans and mice with ABCA1 mutations, who are almost entirely lacking in this lipoprotein species. The other, the cell surface HDL receptor SR-BI, is expressed in hepatocytes and other cell types that consume large amounts of HDL cholesterol. Consistent with the commonly accepted model of reverse cholesterol transport, hepatic overexpression of SR-BI increases cholesterol levels in the bile, whereas deletion of the SR-BI gene dramatically reduces biliary cholesterol secretion. Now, however, a surprising report from Groen et al. shows that mice lacking a functional ABCA1 gene secrete normal levels of cholesterol through the bile, despite the nearly complete absence of plasma HDL. The authors note that another mouse line with low HDL levels, this one lacking the HDL apolipoprotein apoA-I, is also capable of normal biliary cholesterol clearance. As the authors suggest, these findings may force the field to reexamine whether HDL plays a major role in this hepatobiliary route of reverse cholesterol transport. Alternatively, it may be that hepatic uptake of cholesterol packaged in some other form, perhaps as VLDL, increases to compensate for the absence of HDL in these systems.

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