Notes

To investigate the molecular basis of this phenomenon, we generated a strain lacking the heme (iron protoporphyrin IX)-binding protein Dap1 in C
Pharmaceutical intermediates . The Δdap1 mutant displayed growth defects under iron-limited conditions, decreased azole tolerance, decreased production of ergosterol, and increased accumulation of 14α-methylated sterols lanosterol and squalene. All the Δdap1 phenotypes were complemented by wild-type DAP1, but not by DAP1(D91G) , in which a heme-binding site is mutated. Furthermore, azole tolerance of the Δdap1 mutant was rescued by exogenous ergosterol but not by iron supplementation alone. These results suggest that heme binding by Dap1 is crucial for Erg11 activity and ergosterol biosynthesis, thereby being required for azole tolerance. A Dap1-GFP fusion protein predominantly localized to vacuolar membranes and endosomes, and the Δdap1 cells exhibited aberrant vacuole morphologies, suggesting that Dap1 is also involved in the regulation of vacuole structures that could be important for iron storage.

Our study demonstrates that Dap1 mediates a functional link between iron homeostasis and azole resistance in C. glabrata.Hepatic cholesterol metabolism in patients with cholesterol gallstones: enhanced intracellular transport of cholesterol.BACKGROUND & AIMS: Alterations of hepatic cholesterol metabolism in patients with cholesterol gallstones are still controversial. This study investigated whether hepatic cholesterol metabolism is altered in Japanese patients with METHODS: In this systematic study of 24 middle-aged nonobese and nondiabetic Japanese patients who had cholesterol gallstones and were undergoing elective cholecystectomy, an analysis of three regulatory enzymes in the cholesterol metabolism, as well as cytosolic total and free cholesterol levels and sterol carrier protein 2/nonspecific lipid transfer protein (SCP2/nsLTP) levels, was conducted using liver biopsy samples obtained during surgery.RESULTS: The activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA/cholesterol acyltransferase were not significantly different between patients and controls. Nevertheless, patients with gallstones showed tendencies for elevated HMG-CoA reductase activity and protein content and decreased cholesterol 7 alpha-hydroxylase activities.


As anticipated, Pharmaceutical intermediates of 7 alpha-hydroxycholesterol and squalene paralleled these findings. The patients with gallstones also had significantly increased cytosolic total and free cholesterol levels (P < 001), which correlated strongly with increased cytosolic levels of SCP2/nsLTP (r = 00, P < 001 and r = 01, P < 001, CONCLUSIONS: The results suggest that intracellular cholesterol transport is enhanced in patients with cholesterol gallstones.Increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis in freshly isolated hairy cell leukemia cells.Freshly isolated hairy cells from the peripheral blood of patients with hairy cell leukemia (HCL) synthesize 3-5-fold greater amounts of cholesterol, lanosterol, and squalene from [1-14C]-acetate than do normal human peripheral blood mononuclear cells under basal conditions of culture (i.e., in the presence of low-density lipoprotein). HCL cells also exhibit an eightfold increase in the activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase.

These changes cannot be ascribed to increased rates of cellular proliferation in the HCL cells, nor are they a consequence of an increased rate of loss of newly synthesized cholesterol into the culture medium. The increased rate of cholesterol biosynthesis in HCL cells may result in an increase in their total cellular cholesterol content, as well as in an increase in their plasma membrane cholesterol:phospholipid molar ratio. These changes, in turn, are probably responsible for some of the clinical manifestations of this disease.A morphologic and histochemical study of the mesentery in the guinea pig.The guinea pig mesentery is a uniform, continuous, thin (18 micron) sheet of connective tissue covered by a single layer of flattened mesothelial cells on both surfaces. Tight and gap junctions provide for cell-to-cell adhesion among mesothelial cells. These cells possess numerous micropinocytotic vesicles; a conspicuous basal lamina separates the mesothelium from the underlying connective tissue.

Most of the material found between the two serous coverings consisted of a three-dimensional meshwork of abundant collagenous fibers intermingled with a sparse net of very thin (0 micron) elastic fibers. Two distinct populations of collagen fibrils are segregated into different compartments of the mesentery. One population is formed of thick (56 nm) fibrils which associate to form closely packed fibers. The second population, composed of loosely arranged thin (38 nm) fibrils which do not become assembled into fibers, is found underlying the basal lamina that separates the mesothelium from the connective tissue. These observations strongly suggest that the mesentery contains both collagens type I and type III. The guinea pig mesentery contains 6 mg of sulfated glycosaminoglycans/g dry weight. Most of these glycosaminoglycans (78%) were identified as dermatan sulfate, whilst the rest (22%) corresponded to heparan sulfate.

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