Lecithin:cholesterol acyltransferase (LCAT) was isolated from hog plasma and basic physicochemical properties and functionally important regions were investigated. Approximately one milligram of the enzyme was purified to apparent homogeneity with approximately a 20,000-fold increase in specific activity. In the plasma, hog LCAT was found to associate with high-density lipoproteins (HDL) probably through hydrophobic interactions with apolipoprotein A-I. HDL was the preferred lipoprotein substrate of the enzyme as its macromolecular substrate. The enzyme was found to contain 4 free sulfhydryl groups; at least one of these appeared to be essential for catalytic activity. The enzyme had a tendency to aggregate at high concentrations. More than half of the tryptophan and none of the tyrosine residues of the enzyme were shown to be exposed to the aqueous environment based on fluorescence and absorbance studies, respectively.

The purpose of this research was to determine if a high cholesterol diet can affect tie rate of cholesterol synthesis or to cholesterol and fatty acid content of plasma membranes of mouse mammary a.denocarcinoma and normal mouse mammary gland tissue.Cholesterol synthesizing ability was determined by measuring the incorporation of 14C acetate into digitonin-precipitable sterols from both tumors and normal mammary tissue from Strong A Strain female mice fed a standard lab chow diet (control diet; or a 2% cholesterol experimental diet. Plasma membranes were isolated from both tenors and normal tissue by differential centrifugation. Cholesterol was measured spectrophotometrically. Fatty acids were extracted, methylated, and methylesters identified and quantified using gas liquid chromatography.The rate of incorporation of 111C acetate into digitonin-precipitated sterols in normal mammary tissue from mice fed the 2% cholesterol experimental diet was 1.5 times less than controls. Tumor tissue showed no significant difference. The fatty acid composition of tumor and normal mammary tissue plasma membranes from mice fed the 2% cholesterol experimental diet was similar to controls.There were higher percentages of C16:0 and C16.1 in normal plasma membranes of controls than mice fed the experimental diet. Cholesterol content of to or and normal mammary tissue plasma membranes from mice fed the experimental diet was similar to controls.It would appear that dietary cholesterol does have an effect on cholesterol synthesis in normal mammary tissue but not in marina y tumor tissue. Also dietary cholesterol does not have an effect on the fatty acid composition nor the cholesterol content in plasma membranes of mammary tumors or normal mammary tissue.Ball State UniversityMuncie, IN 47306

The objective of this research was to examine the effects of sitosterol and sitostanol supplementation on plasma cholesterol levels and cholesterol metabolism in hypercholesterolemic subjects consuming a fixed foods diet in a four-phase crossover design. It was hypothesized that addition of either phytosterols, phytostenols, or a 50:50 mixture of sterols and stanols to butter would reduce circulating cholesterol levels, despite butter's hypercholesterolemic effect, through actions involving cholesterol absorption, synthesis, and turnover rates. The data obtained indicate that in their free, unesterified form, plant sterols and stanols lower plasma LDL cholesterol equivalently in hypercholesterolemic subjects. Results of this study provide new data that phytosterols and stanols function by suppressing cholesterol absorption while increasing cholesterol synthesis, however, the de-suppression in synthesis cannot fully compensate for the decrease in absorption making the treatment effective, thus may assist in the development of a food which offers health-promoting advantages related to the prevention of cardiovascular disease.

The greatest advances in medicine during the last century have been in the control of infectious diseases. These successes were based fundamentally upon the discoveries of bacteriologists and others of the relation of micro-organisms to disease processes. On the other hand most of the chronic diseases such as, muscular dystrophy, arthritis, cancer and atherosclerosis have not as yet been shown to have any comparable unifying thread to connect them. [...]

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Erratum final three leaves of thesis. / Includes bibliographical references (leaves 266-288). / xvi, 288, [3] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Demonstrates that fatty acids and antioxidants can regulate the low density lipoprotein (LDL) receptor at the level of gene transcription in cultured liver cells. EPA and linoleic acid (PUFAs) are specifically shown to downregulate the LDL receptor compared to saturated and monosaturated fatty acids in the presence or absence of cholesterol. The experiments lead to the discovery that antioxidants can upregulate the LDL receptor in the human HepG2 cells. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1996

Introduction: Increased activation of inflammatory pathways is associated with elevated metabolic stress, which leads to a constellation of metabolic pathologies like fatty liver, insulin resistance and atherosclerosis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a novel transcription co-factor that binds to and inhibits two main pro-inflammatory transcription factors, IRF2 and NFAT1. IRF2BP2 genetic variants are also linked to increased human serum cholesterol level in GWAS studies. Therefore, we hypothesized that IRF2BP2 may inhibit macrophage polarization to pro-inflammatory phenotype and considering the remarkable overlap between inflammatory and metabolic sensors, alter their metabolic function. We sought to determine if specific ablation IRF2BP2 in the mouse myeloid lineage (IRF2BP2MKO) leads to development of metabolic symptoms and alters the risk of atherosclerosis. Results: Our results indicate that IRF2BP2 ablation impairs macrophage polarization to the anti-inflammatory phenotype. IRF2BP2MKO bone marrow derived macrophages (BMDM) show increased oxidized LDL-cholesterol uptake and decreased cholesterol efflux. Also, mice with specific ablation of IRF2BP2 in macrophages are more susceptible to obesity, insulin resistance and hepatic steatosis compared to control mice, when fed high fat diet (HFD). However, LDLR-/- mice transplanted with IRF2BP2MKO bone marrow demonstrate similar extent of atherosclerotic lesions compared to LDLR-/- mice transplanted with control bone marrow, reflecting increased IRF2BP2MKO macrophage apoptosis. Conclusion: In conclusion, this is the first study to identify the metabolic and inflammatory functions of IRF2BP2 protein in macrophages, with important implications in metabolic syndrome and atherosclerosis.

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

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