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...