Biliary cholesterol secretion rates in ABCA1-deficient mice are virtually identical compared with controls (24). The main difference of these two previous selleck catalog reports compared with our present study is that apoA-I knockout mice as well as ABCA1 knockout mice have a defect in HDL formation, whereas with overexpression of EL, we induce a decrease in HDL cholesterol levels by increasing HDL catabolism, resulting in increased hepatic cholesterol content. Experimental animal models in which hepatic SR-BI expression is modulated might represent an exception from the observation that plasma HDL levels are independent from biliary cholesterol secretion. Hepatic SR-BI overexpression resulted in decreased plasma HDL cholesterol levels due to increased catabolism and, in this case, increased biliary cholesterol levels were also noticed (20).
Conversely, in mice with attenuated or absent SR-BI expression, plasma HDL cholesterol levels are increased, while biliary cholesterol secretion is moderately but significantly reduced (27, 44). In our model, biliary cholesterol secretion rates changed with altering hepatic SR-BI expression; however, there was no additional effect of EL. In addition, hepatic SR-BI has been shown to increase RCT from macrophages independent of plasma HDL cholesterol levels (47). These data point toward an important role of the SR-BI expression level within the hepatocyte to provide a link between plasma HDL cholesterol metabolism, hepatic cholesterol uptake, and the subsequent secretion of cholesterol into the bile.
Combined, these studies suggest that plasma HDL cholesterol levels independent from production or catabolism might not be directly related to biliary cholesterol secretion when SR-BI expression is not affected. In summary, our data demonstrate that a virtual elimination of plasma HDL cholesterol due to increased EL-mediated catabolism causes hepatic cholesterol accumulation; however, it does not influence biliary cholesterol secretion. In this setting, biliary cholesterol secretion rates are independent of ABCG5/G8 and depend instead on the hepatic expression level of SR-BI. These data indicate an important role for hepatocyte SR-BI in directing cholesterol toward biliary secretion and stress the relevance of SR-BI in RCT. Supplementary Material Supplemental Data: Click here to view. Acknowledgments The authors thank Dr.
Karen Kozarsky (GlaxoSmithKline, King of Prussia, PA) for providing the SR-BI expressing adenovirus AdSR-BI Brefeldin_A used in this study. The authors are grateful to Drs. Joachim Herz (University of Texas Southwestern, Dallas, TX) and Bart van Vlijmen (Leiden University Medical Center, Leiden, The Netherlands) for p
Acute pancreatitis (AP) is an inflammatory disease characterized by an overall mortality rate of 5%, which reaches 17% for necrotizing pancreatitis.1 At present, no specific medical therapy targeting the inflammatory storm of AP has a proven clinical benefit.