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The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism.
Li, X, Xin, Y, Mo, Y, Marozik, P, He, T, Guo, H
Molecules (Basel, Switzerland). 2022;(2)
Abstract
Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5-2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.
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Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) guidelines for management of dyslipidemia and cardiovascular disease risk reduction: Putting evidence in context.
Al Rifai, M, Blumenthal, RS, Stone, NJ, Schofield, RS, Orringer, CE, Michos, ED, Heidenreich, PA, Braun, L, Birtcher, KK, Smith, SC, et al
Progress in cardiovascular diseases. 2021;:2-6
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the United States (U.S.) and incurs significant cost to the healthcare system. Management of cholesterol remains central for ASCVD prevention and has been the focus of multiple national guidelines. In this review, we compare the American Heart Association (AHA)/American College of Cardiology (ACC) and the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) Cholesterol guidelines. We review the evidence base that was used to generate recommendations focusing on 4 distinct themes: 1) the threshold of absolute 10-year ASCVD risk to start a clinician-patient discussion for the initiation of statin therapy in primary prevention patients; 2) the utility of coronary artery calcium score to guide clinician-patient risk discussion pertaining to the initiation of statin therapy for primary ASCVD prevention; 3) the use of moderate versus high-intensity statin therapy in patients with established ASCVD; and 4) the utility of ordering lipid panels after initiation or intensification of lipid lowering therapy to document efficacy and monitor adherence to lipid lowering therapy. We discuss why the VA/DoD and AHA/ACC may have reached different conclusions on these key issues.
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MicroRNA regulation of cholesterol metabolism.
Citrin, KM, Fernández-Hernando, C, Suárez, Y
Annals of the New York Academy of Sciences. 2021;(1):55-77
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Abstract
MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Since many microRNAs have multiple mRNA targets, they are uniquely positioned to regulate the expression of several molecules and pathways simultaneously. For example, the multiple stages of cholesterol metabolism are heavily influenced by microRNA activity. Understanding the scope of microRNAs that control this pathway is highly relevant to diseases of perturbed cholesterol metabolism, most notably cardiovascular disease (CVD). Atherosclerosis is a common cause of CVD that involves inflammation and the accumulation of cholesterol-laden cells in the arterial wall. However, several different cell types participate in atherosclerosis, and perturbations in cholesterol homeostasis may have unique effects on the specialized functions of these various cell types. Therefore, our review discusses the current knowledge of microRNA-mediated control of cholesterol homeostasis, followed by speculation as to how these microRNA-mRNA target interactions might have distinctive effects on different cell types that participate in atherosclerosis.
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Novel therapeutic approaches for Parkinson's disease by targeting brain cholesterol homeostasis.
Pingale, TD, Gupta, GL
The Journal of pharmacy and pharmacology. 2021;(7):862-873
Abstract
OBJECTIVES Human brain is composed of 25% of the cholesterol & any dysfunction in brain cholesterol homeostasis contributes to neurodegenerative disorders such as Parkinson, Alzheimer's, Huntington's disease, etc. A growing literature indicates that alteration in neurotransmission & brain cholesterol metabolism takes place in the early stage of the disease. The current paper summarizes the role of cholesterol & its homeostasis in the pathophysiology of Parkinson's disease. KEY FINDINGS Literature findings suggest the possible role of lipids such as oxysterols, lipoproteins, etc. in Parkinson's disease pathophysiology. Cholesterol performs a diverse role in the brain but any deviation in its levels leads to neurodegeneration. Dysregulation of lipid caused by oxidative stress & inflammation leads to α-synuclein trafficking which contributes to Parkinson's disease progression. Also, α-synuclein by binding to membrane lipid forms lipid-protein complex & results in its aggregation. Different targets such as Phospholipase A2, Stearoyl-CoA desaturase enzyme, proprotein convertase subtilisin/kexin type 9, etc. have been identified as a potential novel approach for Parkinson's disease treatment. SUMMARY In the current review, we have discussed the possible molecular role of cholesterol homeostasis in Parkinson's disease progression. We also identified potential therapeutic targets that need to be evaluated clinically for the development of Parkinson's treatment.
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Common Genetic Variations Involved in the Inter-Individual Variability of Circulating Cholesterol Concentrations in Response to Diets: A Narrative Review of Recent Evidence.
Abdullah, MMH, Vazquez-Vidal, I, Baer, DJ, House, JD, Jones, PJH, Desmarchelier, C
Nutrients. 2021;(2)
Abstract
The number of nutrigenetic studies dedicated to the identification of single nucleotide polymorphisms (SNPs) modulating blood lipid profiles in response to dietary interventions has increased considerably over the last decade. However, the robustness of the evidence-based science supporting the area remains to be evaluated. The objective of this review was to present recent findings concerning the effects of interactions between SNPs in genes involved in cholesterol metabolism and transport, and dietary intakes or interventions on circulating cholesterol concentrations, which are causally involved in cardiovascular diseases and established biomarkers of cardiovascular health. We identified recent studies (2014-2020) that reported significant SNP-diet interactions in 14 cholesterol-related genes (NPC1L1, ABCA1, ABCG5, ABCG8, APOA1, APOA2, APOA5, APOB, APOE, CETP, CYP7A1, DHCR7, LPL, and LIPC), and which replicated associations observed in previous studies. Some studies have also shown that combinations of SNPs could explain a higher proportion of variability in response to dietary interventions. Although some findings still need replication, including in larger and more diverse study populations, there is good evidence that some SNPs are consistently associated with differing circulating cholesterol concentrations in response to dietary interventions. These results could help clinicians provide patients with more personalized dietary recommendations, in order to lower their risk for cardiovascular disease.
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Cholesterol metabolism and brain injury in neonatal encephalopathy.
Dave, AM, Peeples, ES
Pediatric research. 2021;(1):37-44
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Abstract
Neonatal encephalopathy (NE) results from impaired cerebral blood flow and oxygen delivery to the brain. The pathophysiology of NE is complex and our understanding of its underlying pathways continues to evolve. There is considerable evidence that cholesterol dysregulation is involved in several adult diseases, including traumatic brain injury, stroke, Huntington's disease, and Parkinson's disease. Although the research is less robust in pediatrics, there is emerging evidence that aberrations in cholesterol metabolism may also be involved in the pathophysiology of neonatal NE. This narrative review provides an overview of cholesterol metabolism in the brain along with several examples from the adult literature where pathologic alterations in cholesterol metabolism have been associated with inflammatory and ischemic brain injury. Using those data as a background, the review then discusses the current preclinical data supporting the involvement of cholesterol in the pathogenesis of NE as well as how brain-specific cholesterol metabolites may serve as serum biomarkers for brain injury. Lastly, we review the potential for using the cholesterol metabolic pathways as therapeutic targets. Further investigation of the shifts in cholesterol synthesis and metabolism after hypoxia-ischemia may prove vital in understanding NE pathophysiology as well as providing opportunities for rapid diagnosis and therapeutic interventions. IMPACT This review summarizes emerging evidence that aberrations in cholesterol metabolism may be involved in the pathophysiology of NE. Using data from NE as well as analogous adult disease states, this article reviews the potential for using cholesterol pathways as targets for developing novel therapeutic interventions and using cholesterol metabolites as biomarkers for injury. When possible, gaps in the current literature were identified to aid in the development of future studies to further investigate the interactions between cholesterol pathways and NE.
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Maternal cholesterol levels during gestation: boon or bane for the offspring?
Jayalekshmi, VS, Ramachandran, S
Molecular and cellular biochemistry. 2021;(1):401-416
Abstract
An increase in cholesterol levels is perceived during pregnancy and is considered as a normal adaptive response to the development of the fetus. In some pregnancies, excessive increase in total cholesterol with high levels of Low-Density Lipoprotein leads to maladaptation by the fetus to cholesterol demands, resulting in a pathological condition termed as maternal hypercholesterolemia (MH). MH is considered clinically irrelevant and therefore cholesterol levels are not routinely checked during pregnancy, as a consequence of which there is scarce information on its global prevalence in pregnant women. Studies have reported that MH during pregnancy can cause atherogenesis in adults emphasizing the concept of in utero programming of fetus. Moreover, Gestational Diabetes Mellitus, obesity and Polycystic Ovary Syndrome are potential risk factors which strengthen combined pathologies in placenta and fetuses of mothers with MH. However, lack of conclusive evidence on cholesterol transport and underlying programming demand substantial research to develop population-based life style strategies for women in their childbearing years. The current review focuses on the mechanisms and outcomes of MH from existing epidemiological as well as experimental data and presents a detailed insight on this novel risk factor of cardiovascular diseases.
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Case Report: A Clinical and Genetic Analysis of Childhood Growth Hormone Deficiency With Familial Hypercholesterolemia.
Yang, S, Ke, X, Liang, H, Li, R, Zhu, H
Frontiers in endocrinology. 2021;:691490
Abstract
BACKGROUND Growth hormone deficiency (GHD) is a developmental disorder in children characterized by low growth hormone (GH), short stature and unfavorable lipid profiles. Familial hypercholesteremia (FH) is an inborn disorder of low-density lipoprotein cholesterol (LDL-C) metabolism which results in premature cardiovascular events. The co-occurrence of GHD and FH, which may aggravate the hypercholesteremic condition in the affected individuals, had rarely been discussed in previous publication. METHODS This work reports two cases of GHD with FH, and explores the lipid profiles of GHD children and their therapeutic response to recombinant human growth hormone (rhGH). The diagnosis of GHD is based on low peak GH level (<7 ng/mL) in GH provocation test. FH is diagnosed by high LDL-C level (≥ 4 mmol/L) and confirmed genetic mutations in the LDL-C metabolic pathway. We also searched all previously published metabolic studies on GHD children as of December 31, 2020. Information on their LDL-C, duration and dose of rhGH treatment were retrieved and summarized. RESULTS The first case was a 5.3 year-old boy. His height was 103.6 cm (SDS = -2.29) and his peak GH in provocative test was 6.37 ng/mL. Additionally, his LDL-C was 4.80 mmol/L and he harbored a heterozygous mutation for the apolipoprotein B (APOB) gene (c.10579 C > T). The second case was a 9-year-old girl at the height of 117.3 cm (SDS = -2.91). Her GH peaked at 4.99 ng/mL in insulin-induced hypoglycemic test and 2.80 ng/mL in L-dopa test. Her LDL-C was 6.16 mmol/L, and she carried a mutated copy of the low-density lipoprotein receptor (LDLR) gene (c.809 G > A). Literature review indicated that GHD children suffered from higher baseline LDL-C, but it was significantly reduced after rhGH treatment. CONCLUSIONS FH should be considered if a GHD child has remarkably elevated LDL-C that cannot be attributed to low GH level alone. Genetic mutations in the LDL-C metabolic pathway prevent the body from effectively metabolizing lipids, thereby resulting in early-onset hypercholesteremia and probably playing a negative role in children's growth.
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Cholesterol, lipoproteins, and COVID-19: Basic concepts and clinical applications.
Kočar, E, Režen, T, Rozman, D
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(2):158849
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Abstract
Cholesterol is being recognized as a molecule involved in regulating the entry of the SARS-CoV-2 virus into the host cell. However, the data about the possible role of cholesterol carrying lipoproteins and their receptors in relation to infection are scarce and the connection of lipid-associated pathologies with COVID-19 disease is in its infancy. Herein we provide an overview of lipids and lipid metabolism in relation to COVID-19, with special attention on different forms of cholesterol. Cholesterol enriched lipid rafts represent a platform for viruses to enter the host cell by endocytosis. Generally, higher membrane cholesterol coincides with higher efficiency of COVID-19 entry. Inversely, patients with COVID-19 show lowered levels of blood cholesterol, high-density lipoproteins (HDL) and low-density lipoproteins. The modulated efficiency of viral entry can be explained by availability of SR-B1 receptor. HDL seems to have a variety of roles, from being itself a scavenger for viruses, an immune modulator and mediator of viral entry. Due to inverse roles of membrane cholesterol and lipoprotein cholesterol in COVID-19 infected patients, treatment of these patients with cholesterol lowering statins needs more attention. In conclusion, cholesterol and lipoproteins are potential markers for monitoring the viral infection status, while the lipid metabolic pathways and the composition of membranes could be targeted to selectively inhibit the life cycle of the virus as a basis for antiviral therapy.
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Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression.
Laudanski, K
International journal of molecular sciences. 2021;(19)
Abstract
(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.