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Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Brian Yu, Nikola Sladojevic, James K. Liao
Apart from inhibition of endogenous cholesterol production, the statin-induced reduction of LDL-C modulates LDL receptor trafficking by reducing degradation and upregulating expression of LDL receptors on the cell surface, increasing cholesterol clearance (Goldstein and Brown, 2009). Statin-induced lipoprotein reduction may also include inhibition of hepatic synthesis of apolipoprotein B100, resulting in reduced secretion of apolipoprotein B-containing lipoproteins (Ginsberg et al., 1987). Therefore, aside from directly inhibiting cholesterol biosynthesis, statins may also cause increased clearance of LDL-C from plasma and reduced secretion of triglyceride-rich lipoproteins.
Cell Physiology
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
Cellular uptake of lipids is mediated by receptors of the lipoprotein lipid carriers, by endocytosis of membrane vesicles, or by diffusion. Cells readily take up fatty acids, phospholipids, and cholesterol from the medium and incorporate them into cellular lipids. The cellular uptake of fatty acids is a passive, non-energy-dependent process. After being taken up by cells, fatty acids quickly become esters; the intracellular levels of free fatty acids are quite low. Cholesterol is complexed to low density lipoprotein (LDL) in the body and is taken up by cells through the LDL receptor. For cells in culture, cholesterol is often supplied as a conjugate with serum albumin, or as complexes with cyclodextrin.
Magnetic Nanoparticles for Organelle Separation
Published in Nguyễn T. K. Thanh, Clinical Applications of Magnetic Nanoparticles, 2018
Mari Takahashi, Shinya Maenosono
Endosomes are small membrane vesicles formed by an endocytic process in a cell, during which extracellular materials or receptors on the cell membrane are incorporated. There are two general types of endocytosis: phagocytosis and pinocytosis.37 Phagocytosis takes place actively in phagocytes such as macrophages and monocytes. Pinocytosis is divided into four categories: macropinocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis and clathrin- and caveolae-independent endocytosis. Figure 12.6 shows several endocytic entry ways into a cell.37 Extracellular materials incorporated via endocytosis are transported to lysosomes, resulting in degradation of the materials, or returned to the cellular membrane for recycling of receptors. During this material transport process, endosomes change their state (early endosomes, late endosomes and recycling endosomes). Early endosomes undergo differentiation into late endosomes or recycling endosomes depending on the situation. In the case of receptor-mediated endocytosis, for example, both ligand and receptor are simultaneously incorporated. The ligand is finally transferred to a lysosome, followed by degradation, while the receptor is returned to the cell membrane and reused several hundreds of times by recycling endosomes.38 Endocytosis regulates various cellular processes, including cell motility, cell determination, nutrient uptake and microbial invasion.16 Therefore, functional disorders of endocytosis can cause many diseases such as familial hypercholesterolemia39 and cancer.40 Low-density lipoprotein (LDL) is incorporated into cells via receptor-mediated endocytosis. Patients with familial hypercholesterolemia have dysfunction of the LDL receptor and thus cannot uptake LDL appropriately.39 For this reason, their blood LDL concentration increases, thereby enhancing the potential for arteriosclerosis, which may lead to serious diseases such as myocardial infarction.
Atorvastatin ameliorated PM2.5-induced atherosclerosis in rats
Published in Archives of Environmental & Occupational Health, 2023
Hongmei Yao, Xingxing Zhao, Lili Wang, Yi Ren
In the present study, atorvastatin (ATO), one of the most widely-used statins, was employed to investigate if amelioration of PM2.5-induced atherosclerosis development could be achieved. Statins, the inhibition of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, can effectively decrease the LDL level and meanwhile increase the HDL level.18–20 It is common sense that statins have a lipid-lowering effect. Recently, statins were found to have anti-atherogenic effects, because the lipid-lowering effect of statins could slow the formation of atherosclerotic plaque, suppress smooth muscle cell proliferation and aggregation, reduce the size of atherosclerotic plaques, and prevent from further development of atherosclerotic plaque.21–23 As previously reported, atorvastatin inhibited HMG-CoA reductase and blocked the reaction of HMG-CoA to methylpentanoic acid, which significantly reduces cholesterol synthesis and neutralizes cholesterol concentrations in plasma and tissues.24 Because of the decrease of cholesterol level in the liver, the inhibition of LDL receptor genes was lifted, and thus LDL receptor density in the liver increased, which resulted in high concentrations of LDL molecules in the plasma being taken up and cleared by the liver. As represented in Table 1, in our PM2.5 - atorvastatin treated model, TC, TG, and LDL levels decreased significantly, demonstrating that atorvastatin presented an obvious lipid-lowing effect. Increasing LDL levels could provoke the formation of atherosclerosis by vasoconstriction, inflammation, proliferation of smooth muscle cells, and degradation of collagen fibers.16