Adenovirus-mediated expression of caveolin-1 in mouse liver increases plasma high-density lipoprotein levels

Caveolae are 50-100 nm plasma membrane invaginations, which function in cel l signaling and transcytosis, as well as in regulating cellular cholesterol homeostasis. These subcompartments of the plasma membrane are characterize d by the presence of caveolin proteins. Recent studies have indicated that caveolae may be involved in the regulation of cellular cholesterol efflux t o HDL, as well as selective uptake mediated by SR-Bl. In the present study, we have determined the effect of caveolin-1 overexpression in mouse liver on plasma lipoprotein metabolism. We evaluated this effect using an adenovi rus-mediated gene delivery system. C57BL/6J mice were injected with adenovi ruses encoding either caveolin-1 (Adcav-1) or green fluorescent protein (Ad GFP) together with a transactivator adenovirus (AdtTA). We found that, afte r adenovirus injection, caveolin-1 was overexpressed in hepatocytes. Moreov er, the recombinant protein was localized to the plasma membrane. We also f ound that caveolin-1 overexpression induced a marked change in the lipoprot ein profile of injected animals. In caveolin-1 overexpressing animals, plas ma HDL-cholesterol levels were found to be similar to2-fold elevated, as co mpared with control animals. To determine the effect of caveolin-1 on SR-BI -mediated selective uptake, we infected murine hepatocytes in culture with an adenoviral vector carrying the caveolin-1 cDNA or GFP as a control prote in. We show that, in primary cultures of hepatocytes, caveolin-1 inhibits D iI-HDL uptake mediated by SR-BI. This result would mechanistically explain the increased plasma HDL-cholesterol levels we observed in caveolin-1 adeno virus-injected animals. In addition, caveolin-1 expression increased the se cretion of apolipoprotein A-I in cultured hepatocytes and increased apolipo protein A-I plasma levels in mice. Our study therefore demonstrates an impo rtant role for caveolin-1 in regulating HDL metabolism.