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-ric...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 accumu- lation 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 hypocho-lesterolemic strategies will also be introduced.展开更多
Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to en- vironmental stimuli, and increased susceptibility and vul...Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to en- vironmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery dis- eases, 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 pharmaco- logical 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 sev- eral side effects. More attention should be given to po- tential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as my-opathy and competing risks when statins are prescribed to old patients. In combination or in alternative to sta- tin 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 se- questrants: even these pharmacological interventions are not exempt from side effects. The use of antioxi- dants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL re- ceptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.展开更多
3-hydroxy-3methylglutaryl Coenzyme A reductase, the rate limiting enzyme of mevalonate pathway, generates, in addition to cholesterol, a range of products involved in several biological functions: oligoprenyl groups, ...3-hydroxy-3methylglutaryl Coenzyme A reductase, the rate limiting enzyme of mevalonate pathway, generates, in addition to cholesterol, a range of products involved in several biological functions: oligoprenyl 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 cholesterolemia, 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 myosin heavy chain isoforms. Since we previously demonstrated that chronic statin treatment modifies myosin 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 prescribed to prevent cardiovascular disease, might induce cardiac metabolic and structural modifications whose functional implications on contractility are still to be established and carefully considered.展开更多
文摘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 accumu- lation 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 hypocho-lesterolemic strategies will also be introduced.
文摘Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to en- vironmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery dis- eases, 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 pharmaco- logical 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 sev- eral side effects. More attention should be given to po- tential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as my-opathy and competing risks when statins are prescribed to old patients. In combination or in alternative to sta- tin 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 se- questrants: even these pharmacological interventions are not exempt from side effects. The use of antioxi- dants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL re- ceptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.
文摘3-hydroxy-3methylglutaryl Coenzyme A reductase, the rate limiting enzyme of mevalonate pathway, generates, in addition to cholesterol, a range of products involved in several biological functions: oligoprenyl 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 cholesterolemia, 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 myosin heavy chain isoforms. Since we previously demonstrated that chronic statin treatment modifies myosin 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 prescribed to prevent cardiovascular disease, might induce cardiac metabolic and structural modifications whose functional implications on contractility are still to be established and carefully considered.
