Browsing by Subject "Lipoproteins, LDL"
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Item Causes of high blood cholesterol: implications for treatment(1991-02-07) Grundy, Scott M.Item Does a low plasma cholesterol concentration cause madness?(1994-03-03) Dietschy, John M.Item Elucidating the Anti-Cancer Mechanism of Low Density Lipoprotein-Mediated Delivery of Docosahexaenoic Acid to Hepatocellular Carcinoma Cells(2015-07-17) Moss, Lacy Reynolds; Brown, Kathlynn C.; Corbin, Ian R.; Minna, John D.; Repa, Joyce J.Hepatocellular carcinoma is a lethal malignancy with few effective therapy options. New selective treatments are urgently needed to destroy hepatocellular carcinoma cells without harming the surrounding normal hepatocytes. Recently, docosahexaenoic acid has been shown to possess promising anticancer properties. The Corbin laboratory has incorporated docosahexaenoic acid into low density lipoprotein nanoparticles (LDL-DHA) as a means to transport these fatty acids to cancer cells. To test LDL-DHA's efficacy, immortalized mouse normal liver (TIB-73) and isogeneic malignant liver (TIB-75) cell lines were compared. Cell viability and co-culture experiments demonstrated that TIB-75 cells were more sensitive to LDL-DHA than TIB-73 cells. LDL-DHA enters into cells through LDL receptor-mediated endocytosis to the lysosomes. LDL-DHA treatment increased dichlorofluorescein fluorescence in TIB-75 cells over TIB-73 cells, and generation of reactive oxygen species by menadione sensitized TIB-73 cells to LDL-DHA. Importantly, TIB-75 cells were rescued from LDL-DHA cytotoxicity when antioxidants specific for removing lipid peroxide species were added indicating that lipid peroxidation was critical for LDL-DHA cytotoxicity. LDL-DHA also caused lysosomal membrane permeability of only the TIB-75 cells. Subsequent studies showed that only the LDL-DHA treated TIB-75 cells lose their mitochondrial membrane potential. Mitochondrial reactive oxygen species were elevated in TIB-75 cells following LDL-DHA treatment, and TIB-73 cells were sensitized to LDL-DHA after decoupling of mitochondrial respiration. LDL-DHA treatment also caused DNA damage selectively in the TIB-75 cells. When the Fenton reaction, an iron-catalyzed reaction that generates hydroxyl radicals and lipid peroxide species, was blocked by iron chelation, TIB-75 showed less LDL-DHA cytotoxicity, lipid peroxidation, and lysosome leaking. Studies conducted in human hepatocellular carcinoma cells (FOCUS, Hep3B, and Huh7) on LDL-DHA cytotoxicity, lysosome permeability, and mitochondrial reactive oxygen species production confirmed the findings seen in TIB-75 cells following LDL-DHA treatment. Furthermore, primary human hepatocytes were not sensitive to LDL-DHA treatment. In conclusion, these studies have shown that LDL-DHA is selectively cytotoxic to hepatocellular carcinoma cells and that iron-catalyzed lipid peroxidation sets off a subcellular chain of events resulting in increased reactive oxygen species, lysosome permeability, mitochondrial dysfunction, DNA damage, and, ultimately, cell death in hepatocellular carcinoma cells.Item Low-Density Lipoprotein Receptors in Signaling Modulation and Development(2010-05-14) Dietrich, Martin Frederik; Herz, JoachimThe Low-Density Lipoprotein Receptor gene family is a group of ancient membrane receptors. Originally implied in cargo transport and development of atherosclerosis, the number of members and the diversity of functions have been greatly expanded. LRP1, LRP1b and LRP4 are gene family members that are implicated in the regulation of signaling pathways at the intracellular, extracellular and transcriptional level. These regulations confer viability, control the cellular proliferation at several molecular steps, and allow for proper organ formation by moderating and integrating cellular signaling pathways. / The use of knockin mutant mice has, for the first time, implicated the extracellular domains of LRP1b and LRP4 in signaling modulation in development. While the complete knockout of either receptor is embryonically lethal, the expression of a truncated receptor, spanning only the extracellular domain, confers viability and only a mitigated phenotype. / For LRP4, the difference is most visible in the kidney. The present LRP4 extracellular preserves thresholds critical for organogenesis, yet, the complete absence displays a subpenetrant phenotype of kidney agenesis. In this thesis work, results demonstrate the ability of the LRP4 extracellular domain to not only bind a broad variety of soluble ligands in the extracellular space, but further to influence the Wnt, and possibly others, signaling pathways that are required for kidney development. / In an osteoblast-specific model of LRP1 knock-out, the relationship between theLRP1and the PDGF receptor has been further investigated. LRP1 is known to negatively regulate the PDGF receptor. However, the exact mechanism(s) are not fully understood. In the wild-type, PDGF receptor beta binds directly to LRP1 upon ligand stimulation. LRP1 knockout leads to significant upregulation of the PDGF receptor beta at the protein level. The stimulation of the receptor with PDGF-BB, its corresponding ligand, leads to overactivation of the signaling pathway with both increased turnover and phosphorylation/activation of the receptor, demonstrated by cellular proliferation and p21 downregulation. In vivo, the LRP1 knockout leads to a bone-derived hyperproliferation with formation of tumors at the epiphysis. The in vitro experiments are supporting evidence, combined with previously published literature, to imply the LRP1/PDGF receptor pathway.Item Lowering plasma cholesterol by raising LDL receptors(1981-08-06) Brown, Michael S.Item Regulation of plasma LDL-cholesterol levels(1986-09-11) Dietschy, John M.Item Role of dietary fat and cholesterol in LDL metabolism and atherosclerosis(1990-03-29) Spady, David K.Item [Southwestern News](1995-08-22) McNeill, Bridgette RoseItem [Southwestern News](1996-03-26) Martinez, EmilyItem [UT News](1987-04-24) Bosler, Tommy Joy