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Cholesterol Binding Sites in Inwardly Rectifying Potassium Channels.
Rosenhouse-Dantsker, A
Advances in experimental medicine and biology. 2019;:119-138
Abstract
Inwardly rectifying potassium (Kir) channels play a variety of critical cellular roles including modulating membrane excitability in neurons, cardiomyocytes and muscle cells, and setting the resting membrane potential, heart rate, vascular tone, insulin release, and salt flow across epithelia. These processes are regulated by a variegated list of modulators. In particular, in recent years, cholesterol has been shown to modulate a growing number of Kir channels. Subsequent to the discovery that members of the Kir2 subfamily were down-regulated by cholesterol, we have shown that members of several other Kir subfamilies were also modulated by cholesterol. However, not all cholesterol sensitive Kir channels were down-regulated by cholesterol. Our recent studies focused on three Kir channels: Kir2.1 (IRK1), Kir3.2^ (GIRK2^) and Kir3.4* (GIRK4*). Among these, Kir2.1 was down-regulated by cholesterol whereas Kir3.2^ and Kir3.4* were both up-regulated by cholesterol. Despite the opposite impact of cholesterol on these Kir3 channels compared to Kir2.1, putative cholesterol binding sites in all three channels were identified in equivalent transmembrane domains. Interestingly, however, there are intriguing differences in the specific residues that interact with the cholesterol molecule in these Kir channels. Here we compare and contrast the molecular characteristics of the putative cholesterol binding sites in the three channels, and discuss the potential implications of the differences for the impact of cholesterol on ion channels.
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2018 Guidelines for the management of dyslipidemia.
Rhee, EJ, Kim, HC, Kim, JH, Lee, EY, Kim, BJ, Kim, EM, Song, Y, Lim, JH, Kim, HJ, Choi, S, et al
The Korean journal of internal medicine. 2019;(4):723-771
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Chemical Pathology of Homocysteine VII. Cholesterol, Thioretinaco Ozonide, Mitochondrial Dysfunction, and Prevention of Mortality.
McCully, KS
Annals of clinical and laboratory science. 2019;(4):425-438
Abstract
The purpose of this review is to elucidate how low blood cholesterol promotes mitochondrial dysfunction and mortality by the loss of thioretinaco ozonide from opening of the mitochondrial permeability transition pore (mPTP). Mortality from infections and cancer are both inversely associated with blood cholesterol, as determined by multiple cohort studies from 10 to 30 years earlier. Moreover, low-density lipoprotein (LDL) is inversely related to all-cause and/or cardiovascular mortality, as determined by followup study of elderly cohorts. LDL adheres to and inactivates most microorganisms and their toxins, causing aggregation of LDL and homocysteinylated autoantibodies which obstruct vasa vasorum and produce intimal microabscesses, the vulnerable atherosclerotic plaques. The active site of mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis is proposed to consist of thioretinaco, a complex of two molecules of thioretinamide with cobalamin, oxidized to the disulfonium thioretinaco ozonide and complexed with oxygen, nicotinamide adenine dinucleotide (NAD+), phosphate, and ATP. Loss of the active site complex from mitochondria results from the opening of the mPTP and from decomposition of the disulfonium active site by electrophilic carcinogens, oncogenic viruses, microbes, and by reactive oxygen radicals from ionizing and non-ionizing radiation. Suppression of innate immunity is caused by the depletion of adenosyl methionine because of increased polyamine biosynthesis, resulting in inhibition of nitric oxide and peroxynitrite biosynthesis. Opening of the mPTP produces a loss of thioretinaco ozonide from mitochondria. This loss impairs ATP biosynthesis and causes the mitochondrial dysfunction observed in carcinogenesis, atherosclerosis, aging and dementia. Cholesterol inhibits the opening of the mPTP by preventing integration of the pro-apoptotic Bcl-2-associated X protein (BAX) in the outer mitochondrial membrane. This inhibition explains how elevated LDL reduces mitochondrial dysfunction by preventing loss of the active site of oxidative phosphorylation from mitochondria.
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Steroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation.
Tugaeva, KV, Sluchanko, NN
Biochemistry. Biokhimiia. 2019;(Suppl 1):S233-S253
Abstract
Steroidogenesis takes place mainly in adrenal and gonadal cells that produce a variety of structurally similar hormones regulating numerous body functions. The rate-limiting stage of steroidogenesis is cholesterol delivery to the inner mitochondrial membrane, where it is converted by cytochrome P450scc into pregnenolone, a common precursor of all steroid hormones. The major role of supplying mitochondria with cholesterol belongs to steroidogenic acute regulatory protein (STARD1). STARD1, which is synthesized de novo as a precursor containing mitochondrial localization sequence and sterol-binding domain, significantly accelerates cholesterol transport and production of pregnenolone. Despite a tremendous interest in STARD1 fueled by its involvement in hereditary diseases and extensive efforts of numerous laboratories worldwide, many aspects of STARD1 structure, functioning, and regulation remain obscure and debatable. This review presents current concepts on the structure of STARD1 and other lipid transfer proteins, the role of STARD1 in steroidogenesis, and the mechanism of its functioning, as well as identifies the most controversial and least studied questions related to the activity of this protein.
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The 2018 AHA/ACC/Multi-Society Cholesterol guidelines: Looking at past, present and future.
Stone, NJ, Grundy, SM
Progress in cardiovascular diseases. 2019;(5):375-383
Abstract
The authors review more than three decades of progress in providing clinicians and patients with guidance on risk assessment, patient evaluation and cholesterol management. Beginning with the National Cholesterol Education Program's Initial Adult Treatment Panel report, the cholesterol guidelines increasingly reflect the progress made in understanding the benefits of improved lifestyle and nutrition to improve lipid profiles, major risk factors and reduce ASCVD risk. Moreover, they now provide qualitative and quantitative assessment tools to guide appropriate risk reduction LDL-C lowering therapy. Use of the Pooled Cohort Equations to determine Low, Borderline, Intermediate and High 10-year ASCVD risk is now joined by recognition of conditions and biomarkers that enhance ASCVD risk. This personalizes the risk discussion for the patient. An important addition is the selective use of coronary artery calcium (CAC) scoring to reclassify risk in patients at borderline or intermediate risk, but for whom a risk decision regarding statin therapy is uncertain. In secondary prevention, current guidelines provide criteria for determining a "very high" risk group in whom risk is especially high and in whom aggressive LDL-C lowering can be shown to provide increased absolute benefit. Current guidelines provide a comprehensive look at children and adolescents, young adults, elderly, women and issues specific to women through the life course. They provide guidance for those adults at risk due to severe hypercholesterolemia, persistent hypertriglyceridemia after secondary causes have been addressed, those with inflammatory disorders and HIV, those adults with chronic kidney disease, and those affected by issues of race/ethnicity. They conclude with a brief summary of recommendations emphasizing important concepts for providing safety with LDL-C lowering therapy. This combination of best external evidence and clinical expertise from the expert panel should provide a solid foundation for lipid management of patients at risk for or with clinical ASCVD.
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Nutrigenetics of Blood Cholesterol Concentrations: Towards Personalized Nutrition.
Vazquez-Vidal, I, Desmarchelier, C, Jones, PJH
Current cardiology reports. 2019;(5):38
Abstract
PURPOSE OF THE REVIEW To summarize achievements made in the field of nutrigenetics to personalized nutrition. Moreover, the limitations and challenges observed to enable clinical utilization are discussed. RECENT FINDINGS Currently, with the availability of low-cost genetic testing and new bioinformatics tools, significant developments have occurred to allow issues inherent to the highly complex nature of genetic data to be tackled. Moreover, new statistical methods have uncovered combinatory patterns of SNPs that collectively explain the high interindividual variability in response to dietary interventions. Yet, the application of these results to personalized dietary recommendations is not straightforward. Data from gene-nutrient interaction studies have provided evidence to understand the inter-individual variation differences in blood cholesterol responses. A need exists for guidelines and regulations in order to apply nutrigenetics to personalized nutrition. Moreover, a multisystem approach including genetics, microbiome and environment is needed to achieve possible practical applications.
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Lipid mediators of liver injury in nonalcoholic fatty liver disease.
Liangpunsakul, S, Chalasani, N
American journal of physiology. Gastrointestinal and liver physiology. 2019;(1):G75-G81
Abstract
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathological phenotypes ranging from simple steatosis to more severe liver disease associated with cell injury, including nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. Only a subset of patients with NAFLD develop NASH from yet incompletely understood mechanisms. Emerging data suggest lipid species other than triglycerides as contributors to the pathogenesis of NASH. In this mini review, we focus on the recent data on the mechanisms of NASH, focusing on these lipid mediators and their potential as therapeutic targets in NASH.
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Cholesterol Peroxidation as a Special Type of Lipid Oxidation in Photodynamic Systems.
Girotti, AW, Korytowski, W
Photochemistry and photobiology. 2019;(1):73-82
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Abstract
Like other unsaturated lipids in cell membranes and lipoproteins, cholesterol (Ch) is susceptible to oxidative modification, including photodynamic oxidation. There is a sustained interest in the pathogenic properties of Ch oxides such as those generated by photooxidation. Singlet oxygen (1 O2 )-mediated Ch photooxidation (Type II mechanism) gives rise to three hydroperoxide (ChOOH) isomers: 5α-OOH, 6α-OOH and 6β-OOH, the 5α-OOH yield far exceeding that of the others. 5α-OOH detection is relatively straightforward and serves as a definitive indicator of 1 O2 involvement in a reaction, photochemical or otherwise. Like all lipid hydroperoxides (LOOHs), ChOOHs can disrupt membrane or lipoprotein structure/function on their own, but subsequent light-independent reactions may either intensify or attenuate such effects. Such reactions include (1) one-electron reduction to redox-active free radical intermediates, (2) two-electron reduction to redox-silent alcohols and (3) translocation to other lipid compartments, where (1) or (2) may take place. In addition to these effects, ChOOHs may act as signaling molecules in reactions that affect cell fates. Although processes a-c have been well studied for ChOOHs, signaling activity is still poorly understood compared with that of hydrogen peroxide. This review focuses on these various aspects Ch photoperoxidation and its biological consequences.
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[Translational Research Based on Understanding the Regulatory Mechanisms of in Vivo Behaviors of Fat-soluble Compounds].
Yamanashi, Y
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2019;(12):1485-1494
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Abstract
Several fat-soluble compounds such as cholesterol and fat-soluble vitamins have important physiological activities in the body, and their excess and/or deficiency have been reported to be closely associated with the onset and progression of several conditions such as lifestyle-related diseases. It is important to clarify not only the physiological activities but also in vivo kinetics of fat-soluble compounds to understand their in vivo activity (toxicity). This review introduces our recent (reverse) translational research in a combination of basic and clinical studies to reveal the regulatory mechanisms of in vivo behaviors of fat-soluble compounds and effects of their disruption in humans.
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High-density lipoprotein functionality and breast cancer: A potential therapeutic target.
Samadi, S, Ghayour-Mobarhan, M, Mohammadpour, A, Farjami, Z, Tabadkani, M, Hosseinnia, M, Miri, M, Heydari-Majd, M, Mehramiz, M, Rezayi, M, et al
Journal of cellular biochemistry. 2019;(4):5756-5765
Abstract
Breast cancer is a major cause of death globally, and particularly in developed countries. Breast cancer is influenced by cholesterol membrane content, by affecting the signaling pathways modulating cell growth, adherence, and migration. Furthermore, steroid hormones are derived from cholesterol and these play a key role in the pathogenesis of breast cancer. Although most findings have reported an inverse association between serum high-density lipoprotein (HDL)-cholesterol level and the risk of breast cancer, there have been some reports of the opposite, and the association therefore remains unclear. HDL is principally known for participating in reverse cholesterol transport and has an inverse relationship with the cardiovascular risk. HDL is heterogeneous, with particles varying in composition, size, and structure, which can be altered under different circumstances, such as inflammation, aging, and certain diseases. It has also been proposed that HDL functionality might have a bearing on the breast cancer. Owing to the potential role of cholesterol in cancer, its reduction using statins, and particularly as an adjuvant during chemotherapy may be useful in the anticancer treatment, and may also be related to the decline in cancer mortality. Reconstituted HDLs have the ability to release chemotherapeutic drugs inside the cell. As a consequence, this may be a novel way to improve therapeutic targeting for the breast cancer on the basis of detrimental impacts of oxidized HDL on cancer development.