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In two of 12 patients with clinical glucocorticoid resistance, mutant forms of GR could be found. The glucocorticoid resistance in vivo in these two patients corresponds to impaired function of the two mutated GR forms in two in vitro assays. The relevance of the conservative polymorphism for the glucocorticoid insensitivity noted in these patients remains to be clarified.

Fibrates are a group of hypolipidemic agents that efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor ␣ (PPAR␣). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPAR␣ and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12␣-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for 1 week with the peroxisome proliferator WY-14,643 or fasting for 24 h both induced the sterol 12␣-hydroxylase mRNA in liver. Using the PPAR␣ knockout mouse model, we show that the induction by both treatments was dependent on the PPAR␣. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12␣-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPAR␣ expression plasmid. The rat 12␣-hydroxylase PPRE bound in vitro translated PPAR␣ and retinoid X receptor ␣, albeit weakly, in electrophoretic mobility shift assay. Treatment of wild-type mice with WY-14,643 for 1 week resulted in an increased relative amount of cholic acid, an effect that was abolished in the PPAR␣ null mice, verifying the functionality of the PPRE in vivo.Fibrates and their derivatives constitute a group of hypolipidemic agents that are used in the treatment of hypertriglyceridemia and combined hyperlipidemia. These fibrates belong to a structurally diverse group of compounds known as peroxisome proliferators, which have been shown to cause liver hepatomegaly, proliferation of peroxisomes, and induction of many enzymes involved in peroxisomal and mitochondrial ␤-oxidation and -oxidation of fatty acids (for review, see Ref.

The very low density lipoprotein (VLDL) receptor binds apolipoprotein E-rich lipoproteins as well as the 39-kDa receptor-associated protein (RAP). Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells. To gain insight into the role of the VLDL receptor in the vascular endothelium, its ligand binding properties were further characterized. In vitro binding experiments documented that lipoprotein lipase (LpL), a key enzyme in lipoprotein catabolism, binds with high affinity to purified VLDL receptor. In addition, urokinase complexed with plasminogen activator-inhibitor type I (uPA⅐PAI-1) also bound to the purified VLDL receptor with high affinity. To assess the capacity of the VLDL receptor to mediate the cellular internalization of ligands, an adenoviral vector was used to introduce the VLDL receptor gene into a murine embryonic fibroblast cell line deficient in the VLDL receptor and the LDL receptorrelated protein, another endocytic receptor known to bind LpL and uPA⅐PAI-1 complexes. Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125 I-labeled LpL and uPA⅐PAI-1 complexes, leading to their degradation. Non-infected fibroblasts or fibroblasts infected with the lacZ gene did not internalize these ligands. These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA⅐PAI-1 complexes. Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor. The low density lipoprotein (LDL)1 receptor gene family includes the LDL receptor (1), the very low density lipoprotein (VLDL) receptor (2), the LDL receptor-related protein (LRP) (3), and glycoprotein 330 (4). Together, these molecules have important roles in the catabolism of lipoproteins, proteinases, proteinase-inhibitor complexes, and matrix proteins (for reviews, see Refs. 5-8). The members of this receptor family share structural motifs including cysteine-rich epidermal growth factor-like repeats, cysteine-rich ligand binding repeats, repeats containing the tetrapeptide sequence tyrosinetryptophan-threonine-aspartic acid, and an asparagine-proline-X-tyrosine sequence within the cytoplasmic tail, which is responsible for endocytic signaling in coated pits.The most recently identified member of this receptor family is the VLDL receptor (2), so named because it appeared to specifically bind VLDL, probably via interaction with apolipoprotein E (apo E). At present, however, the physiological role of the VLDL receptor is uncertain. This receptor is most abundant in skeletal muscle, heart, adipose tissue, and brain (9 -11), tissues which metabolize fatty acids as an energy source. This fact, and the observation that the V...

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