Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased adrenal HDL-CE clearance from 33-58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38-52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical .4-fold increased tumor necrosis factor-a response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal adrenal function.-Hoekstra, M., D. Ye, R. B. Hildebrand, Y. Zhao, B. Lammers, M. Stitzinger, J. Kuiper, T. J. C. Van Berkel, and M. Van Eck. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocor ticoid production.

Liver parenchymal cells play a dominant role in hepatic metabolism and thereby total body cholesterol homeostasis. To gain insight into the specific pathways and genes involved in the response of liver parenchymal cells to increased dietary lipid levels under atherogenic conditions, changes in parenchymal cell gene expression upon feeding a Western-type diet for 0, 2, 4, and 6 weeks were determined using microarray analysis in LDL receptor-deficient mice, an established atherosclerotic animal model. Using ABI Mouse Genome Survey Arrays, we were able to detect 7,507 genes (28% of the total number on an array) that were expressed in parenchymal cells isolated from livers of LDL receptordeficient mice at every time point investigated. Timedependent gene expression profiling identified fatty acid binding protein 5 (FABP5) and four novel FABP5-like transcripts located on chromosomes 2, 8, and 18 as important proteins in the primary response of liver parenchymal cells to Western-type diet feeding, because their expression was 16-to 22-fold increased within the first 2 weeks on the Westerntype diet. The rapid substantial increase in gene expression suggests that these FABPs may play an important role in the primary protection against the cellular toxicity of cholesterol, free fatty acids, and/or lipid oxidants. Furthermore, as a secondary response to the Western-type diet, liver parenchymal cells of LDL receptor-deficient mice stimulated glycolysis and lipogenesis pathways, resulting in a steady, more atherogenic serum lipoprotein profile (increased VLDL/LDL). High levels of circulating cholesterol attributable to the consumption of Western-type/high-fat diets form a major risk factor for atherosclerosis and subsequent cardiovascular diseases (e.g., myocardial infarction, stroke) (1), which are the leading causes of death in the Western world. Several mutations in the LDL receptor are associated with familial hypercholesterolemia, a dominantly inherited error of metabolism characterized by increased plasma LDL levels, xanthomas of skin and tendons, and premature heart disease caused by atherosclerosis of the coronary arteries (2).The liver is an essential organ in the regulation of serum cholesterol levels because it is able to clear excess cholesterol from the blood for subsequent excretion into the bile (3, 4). In addition, the liver is responsible for the synthesis and secretion of VLDL and HDL, respectively (5, 6). Because of the important role of the liver in the control of serum cholesterol levels, several studies have recently been conducted using microarray technology to determine the molecular mechanisms underlying long-term high-fat dietinduced alterations in total mouse liver (7-9). However, a common problem with these types of microarray studies is the heterogeneity of the liver, which contains several different cell types, each of which has its specific localization and function. Kupffer cells are tissue macrophages strategically located within the liver sinusoids, and their function is the remova...

In order to form distant metastases, cells from the primary tumor have to detach, enter the blood- or lymph-compartment and escape immune surveillance. Here, we describe the selection of rat colon carcinoma cell lines (CC531s-m1 and CC531s-m2) that escaped from systemic immune surveillance; CC531s cells were injected into the v. jugularis of Wag/Rij rats, after three weeks the lung tumors were isolated, the tumor cells were cultured, characterized and injected again. The m1- and m2-cell lines were less susceptible for killing by syngeneic NK cells. Further characterization of this cell line showed a decreased sensitivity towards TRAIL- and CD95L-, but not to granzyme B-mediated apoptosis. In the m1- and m2-cells log-phase growth started earlier as compared to the parental cell line, whereas no changes were found in anchorage-dependent or anchorage-independent growth. After subcapsular injection of the m2-cell line into the liver of rats much more lung metastases were formed in comparison to injection of the parental cell line. In conclusion, the results suggest that the resistance of the m1- and m2-cells to NK cell-mediated apoptosis was associated with their capability to survive systemic immune surveillance and form metastases in vivo.

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