1,721,062 research outputs found
Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic "power station"
No full textCholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumulation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocholesterolemic strategies will also be introduced.Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumulation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocholesterolemic strategies will also be introduced. © 2012 Baishideng
New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?
No full text""Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg\\\/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.. . "
Regulation of cholesterol biosynthetic pathway in different regions of the rat central nervous system
No full text""Aim: In this study, we investigated the regulatory network of the key and. rate-limiting enzyme of cholesterol biosynthetic pathway, the 3-hydroxy. 3-methylglutaryl coenzyme A reductase (HMGR) in different brain. regions, to add new insight about lipid metabolism and physiology in the. central nervous system (CNS).. Methods: HMGR levels and activation state and the proteins involved in. the enzyme regulatory network were analysed by Western blot in hippocampus,. cortex, cerebellum and brain stem of adult male rats.. Results: HMGR protein level and phosphorylation state exhibit a specific. pattern in each brain area analysed, according to the levels and activation. state of the proteins responsible for the short- and long-term regulation of. the enzyme. Moreover, low-density lipoprotein receptor expression displays. a similar trend to that of HMGR.. Conclusions: The obtained data indicate that cholesterol biosynthesis. could be differently modulated in each brain region in adult male rat and. emphasize marked differences in HMGR and low-density lipoprotein. receptor regulation. The results provide new insights into the intricate. network that regulates cholesterol homoeostasis in the adult CNS in. connection with the regional needs of this molecule.. Keywords central nervous system, cholesterol, HMG-CoA reductase."
Potential role of nonstatin cholesterol lowering agents
No full text""Although statins, 3b-hydroxy-3b-methylglutaryl coenzyme A. reductase (HMGR) inhibitors, have revolutionized the management. of cardiovascular diseases by lowering serum low density. lipoproteins, many patients suffer from their side effects.. Whether the statin side effects are related to their intrinsic toxicity. or to the decrease of HMGR main isoprenoid end products,. which are essential compounds for cell viability, is still. debated. In addition to HMGR, the key and rate limiting step. of cholesterol synthesis, many enzymes are involved in this. multi-step pathway whose inhibition could be taken into. account for a ‘‘nonstatin approach’’ in the management of. hypercholesterolemia. In particular, due to their unique position. downstream from HMGR, the inhibition of squalene synthase,. farnesyl diphosphate farnesyltransferase (FDFT1), squalene. epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase. (OSC) should decrease plasma levels of cholesterol without. affecting ubiquinone, dolichol, and isoprenoid metabolism.. Thus, although FDFT1, SQLE and OSC are little studied, they. should be considered as perspective targets for the development. of novel drugs against hypercholesterolemia. Here, structure–. function relationships of FDFT1, SQLE, and OSC are reviewed. highlighting the advantages that the downstream inhibition of. HMGR could provide when compared to the statin-based. therapy."
Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor
No full text""To determine whether differences in LDLr behavior in extra-hepatic tissues and whether extra-hepatic receptors could differentially. contribute to cholesterol homeostasis under physiological conditions, we evaluated the presence and regulation of LDLr from both a. gender and an aging perspective. We used the brain cortex, the gastrocnemius, and the heart ventricle of 3- and 12-month-old male and. female rats. We observed a protein decrease of total LDLr in 12-month-old female rat brains that was completely restored by 17-b. estradiol treatment. In the gastrocnemius, LDLr accumulates in the skeletal muscle in both male and female aged rats as a precursor. probably due to a glycosylation impairment. In the heart, no modifications were observed in either older rats or rats of a specific gender.. These data highlight a tissue-specific dysregulation of LDLr that is age- and gender-dependent."
Nasal expression of the vascular endothelial growth factor and its receptors is reduced by mepolizumab in chronic rhinosinusitis with nasal polyposis
No full textChronic rhinosinusitis with nasal polyposis (CRSwNP) is a phenotype of chronic rhinosinusitis characterized by the presence of nasal polyps. To date, medical therapy and surgery can manage the disease in most of the cases. However, despite improvements in surgical techniques, CRSwNP is characterized by relapses in severe cases, thus leading to the study of biological drugs such as Mepolizumab, antagonizing IL-5. Experimental and clinical evidence demonstrates that CRSwNP is driven by a type 2 immune response and displays eosinophil infiltration, mucosal inflammation, and hyperplasia of the epithelium. Besides, it has been described that vascular endothelial growth factor (VEGF) is strongly upregulated in the mucosa of CRSwNP patients, promoting edema and epithelial cell growth in nasal polyps when compared to normal mucosa. Notably, other reports demonstrated that IL-5 stimulates VEGF production, which may influence immune cells’ activity in inflammatory conditions
HMG CoA reductase inhibition by Simvastatin gets rat β-Myosin heavy chain disappeared: A statin paradox.
No full text""3-hydroxy-3methylglutaryl Coenzyme A reductase, the rate limiting enzyme of mevalonate pathway, generates, in addition to cholesterol, a range of prod- ucts involved in several biological functions: oligo- prenyl groups, dolichol and ubiquinone. The latter, in particular, participates in electron transport chain and, in turn, in tissue energy supply. The enzyme is inhibited by statins that, besides lowering choles- terolemia, seem to impair human energy-dependent myocardial functions (e.g. stroke volume, cardiac output, and contractile index). The modulation of heart contractile properties could be explained by the decrease of ventricle ubiquinone content and\\\/or by putative changes in proportion of the different my- osin heavy chain isoforms. Since we previously dem- onstrated that chronic statin treatment modifies my- osin heavy chain isoform pattern in skeletal muscle impairing its functional properties, this work was aimed at investigating the effects of statin chronic treatment on both ventricle ubiquinone content and myosin heavy chain isoforms. Our results showed that simvastatin treatment leads to a reduced amount of rat ventricle ubiquinone and to β myosin heavy chain disappearance. Thus, statins which are pre- scribed to prevent cardiovascular disease, might in- duce cardiac metabolic and structural modifications whose functional implications on contractility are still to be established and carefully considered."
Cholesterol homeostasis failure in the brain: implications for synaptic dysfunction and cognitive decline
No full textCholesterol is one of the most important molecules in cell physiology because of its involvement in several biological processes: for instance, it determines both physical and biochemical properties of cell membranes and proteins. Disruption to cholesterol homeostasis leads to coronary heart disease, atherosclerosis and metabolic syndrome. Strong evidence suggests that cholesterol also has a crucial role in the brain as various neurological and neurodegenerative disorders, including Alzheimer's, Huntington's and Parkinson diseases are associated with disruptions to cholesterol homeostasis. Here, we summarize the current knowledge about the role cholesterol plays at synaptic junctions and the pathological consequences caused by disruptions in the homeostatic maintenance of this compound
3-Hydroxy 3-methylglutaryl Coenzyme A reductase. Regulation by antioxidant compounds: new therapeutic tools for hypercholesterolemia ?
No full text""Oxidative stress has recently been implicated in the pathogenesis of various diseases such as diabetes and coronary artery disease whose main modifiable risk factor is the abnormal level of lipids and\\\/or lipoproteins in the blood. Thus, the maintenance of cholesterol homeostasis together with the reduction of intracellular reactive oxygen species content could partially prevent the occurrence of atherosclerotic phenomena.. Owing to the ability exerted by some antioxidants to modulate the activity and\\\/or the protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (the rate-limiting enzyme of cholesterol biosynthetic pathway), their use as additional approach to the management of hypercholesterolemia should be taken into account. . Here we provide an up-dated overview of the antioxidants whose ability to affect 3-hydroxy-3-methylglutaryl coenzyme A reductase either in the short- or in the long-term regulations has been reported.. . "
Fat Checking: Emerging Role of Lipids in Metabolism and Disease
Full text linkLipids are hydrophobic molecules involved in a plethora of biological functions; for example, they are employed for the storage of energy, serve as essential constituents of cell membranes and participate in the assembly of bilayer configuration [...
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