Hepatic Overexpression of Caveolins Increases Bile Salt Secretion in Mice

Caveolins are cholesterol–binding proteins involved in the regulation of several intracellular processes, including cholesterol transport. Because hepatocytes express caveolin–1 and caveolin–2, these proteins might modulate hepatic lipid metabolism and biliary lipid secretion. Our aim was to investigate the potential physiologic role of caveolins in hepatic cholesterol and bile salt (BS) metabolism and transport using adenoviral gene transfer. C57BL/6 mice were infected with recombinant human caveolin–1 and caveolin–2 adenoviruses. Mice infected with adenovirus lacking the transgene were used as controls. Hepatic caveolin expression was evaluated by immunochemical methods. Reverse–transcription polymerase chain reaction (RT–PCR) and immunoblotting were used to assess messenger RNA (mRNA) levels and protein mass of BS transporters (sodium taurocholate cotransporting polypeptide [Ntcp] and bile salt export pump [Bsep]). Serum, liver, biliary, and fecal biochemical determinations and BS maximal secretory rate (SRm) were performed by standard methods. Ad.Cav–1– and Ad.Cav–2–infected mice exhibited a 10– and 7–fold increase in hepatic caveolin–1 and caveolin–2 protein expression, respectively. Caveolin–1–overexpressing mice had a significant increase in plasma high–density lipoprotein (HDL) cholesterol and hepatic free cholesterol content, whereas total plasma cholesterol and triglyceride levels remained unchanged. Hepatic caveolin–1 and/or caveolin–2 overexpression significantly increased bile flow and secretion of all biliary lipids. Caveolin–1–overexpressing mice showed a 2.5–fold increase in taurocholate (TC) SRm, indicating increased canalicular BS transport capacity. BS pool size and fecal BS excretion remained within the normal range in mice with Cav–1 overexpression. No changes were seen in the protein mass of BS transporters Ntcp and Bsep. In conclusion, our findings indicate that caveolins may play an important role in regulating hepatic BS and cholesterol metabolism.