Mevalonate inhibition
Encyclopedia
Mevalonate inhibition is used to define the effects of medicines based on HMG-CoA reductase
enzyme inhibitor
s to control the products of the mevalonate pathway. This term addresses the effects of long-term restriction of mevalonate production in cell membranes by the inhibition of the membrane attached enzyme HMG-CoA reductase
. Such inhibitors are also known as the statins. They exert their effect at the very beginning of the mevalonate pathway, the location of this key reductase
step, and thereby reduce the de-novo availability of a range of terpenoid
and steroid
products in cell membrane
. The consequences of long-term statin use are classified below according to the depletion of a mevalonate product, e.g. de novo membrane cholesterol. and Co-enzyme Q10
There are also less direct impacts from mevalonate product depletions e.g. those affecting the synthesis of Tau proteins and Rho family of GTPases
to consider here.
A key example is the is glial cell
cholesterol synthesis in our brain
s vital for memory function and cognition
.
Cholesterol also is the substrate for our most important hormones: aldosterone
, cortisone
, estrogen
, progesterone
and testosterone
as well as the quasi
-hormone
, vitamin D
(calciferol). The body itself produces all the cholesterol it needs and there is no requirement for any dietary cholesterol intake.
Cholesterol's vital role in eukaryote
biomembrane structure
and function and lipid raft
formation, makes it of critical importance in vesicle
formation, exocytosis
, endocytosis
, lipid
trafficking
cell signalling, cell communication and immune defense.
Potential adverse effects of glial cell
inhibition of de novo cholesterol synthesis include amnesia
, forgetfulness, confusion, disorientation and increased senility.
.
An oligodendrocyte
runs numerous processes to continuously replace oxidised cholesterol (Oxycholesterol
) in the myelin sheathing of up to 40 neurons. Treatments that lower LDL cholesterols such as (APOE
), by mevalonate inhibition are known to impair myelin maintenance in oligodendrocytes, leading to Neurodegeneration
and dementia
.
. Golomb et al. have extensively reviewed and documented the role of statin side effects and very strongly associated them with CoQ10 depletion. A direct causative biochemical link has been in the long term use HMG-CoA reductase
and the depletion of the mevalonate required for the biosynthesis of mitochondrial CoQ10.
The correction of this deficiency is discussed in the documentation supporting two US patent applications (Nos.4,933,165 and 4,929,437) for the inclusion of CoQ10 in statin medication both filed in 1990.
A citizen's petition for improved guidance on CoQ10 supplementation was undertaken by a journal of the Life Extension Foundation
in 2002 and remains unresolved.
Mitochondrial Damage, Permanent Neuropathy, Permanent Myopathy
, Neurodegeneration
s are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein
formation in the endoplasmic reticulum
of cells. In this capacity it is critical to the formation of the Glycoprotein
s involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability
of dolichols can affect every cellular process in the body.
Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense.
is interfered with by mevalonate blockade, our cells increase the production of tau protein
. Tau is the protein substance of the neurofibrillary tangle
s common to Alzheimer's disease
and other neurodegenerative diseases
.
Abnormal tau phosphorylation and deposition in neuron
s and glial cells is one of the major features in tauopathies
.
The tauopathies are a group of neurodegenerative disorders characterized by the presence of filamentous deposits, consisting of hyperphosphorylated
tau protein, in neurons and glia.
Major neurodegenerative tauopathies includes sporadic and hereditary neurodegenerative diseases characterized by filamentous tau deposits in brain and spinal cord.
In prototypical tauopathies, glial and neuronal tau inclusions are the sole or predominant CNS lesions. They include
Section References:
Alzheimer's and Parkinson Disease 9Th International Conference
are just emerging. Deficiency of selenoproteins has been proven to result in various types of Myopathies formerly seen only in Selenium deficiency
- ( a Trace element
). Additionally some forms of cognitive dysfunction
are associated with Selenium deficiency
.
and immunomodulation effect of statins might be mediated by such statin inhibition of NF-κB. Repoerted improvement in atherosclerosis
may result from such inhibition of the key inflammatory elements: smooth muscle migration. lymphocyte adhesion, macrophage attraction and platelet activation has been associated with inhibition of NF-κB. The immunodefense system is also keyed to NF-κB, possibly explaining associative connections with changing patterns of certain infections and cancers.
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
enzyme inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
s to control the products of the mevalonate pathway. This term addresses the effects of long-term restriction of mevalonate production in cell membranes by the inhibition of the membrane attached enzyme HMG-CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
. Such inhibitors are also known as the statins. They exert their effect at the very beginning of the mevalonate pathway, the location of this key reductase
Reductase
-Examples:* 5-alpha reductase* Dihydrofolate reductase* HMG-CoA reductase* Methemoglobin reductase* Ribonucleotide reductase* Thioredoxin reductase* E. coli nitroreductase* Methylenetetrahydrofolate reductase...
step, and thereby reduce the de-novo availability of a range of terpenoid
Terpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
and steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
products in cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. The consequences of long-term statin use are classified below according to the depletion of a mevalonate product, e.g. de novo membrane cholesterol. and Co-enzyme Q10
There are also less direct impacts from mevalonate product depletions e.g. those affecting the synthesis of Tau proteins and Rho family of GTPases
Rho family of GTPases
The Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...
to consider here.
Cholesterol depletion in cholesterol-rich lipid rafts
Cholesterol produced and found in the membranes of eukaryotic cells where it is facilitates their form and function.A key example is the is glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
cholesterol synthesis in our brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s vital for memory function and cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
.
Cholesterol also is the substrate for our most important hormones: aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
, estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
as well as the quasi
Quasi
Quasi is an American indie rock band formed in Portland, Oregon in 1993 by ex-husband and wife Sam Coomes and Janet Weiss . Since 2007 the group has been a trio, following the addition of bassist Joanna Bolme.-History:In 1990 , Coomes, Weiss, and Brad Pedinov formed the band Motorgoat...
-hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
, vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
(calciferol). The body itself produces all the cholesterol it needs and there is no requirement for any dietary cholesterol intake.
Cholesterol's vital role in eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
biomembrane structure
Structure
Structure is a fundamental, tangible or intangible notion referring to the recognition, observation, nature, and permanence of patterns and relationships of entities. This notion may itself be an object, such as a built structure, or an attribute, such as the structure of society...
and function and lipid raft
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
formation, makes it of critical importance in vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
formation, exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
, endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
trafficking
cell signalling, cell communication and immune defense.
Potential adverse effects of glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
inhibition of de novo cholesterol synthesis include amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
, forgetfulness, confusion, disorientation and increased senility.
.
An oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
runs numerous processes to continuously replace oxidised cholesterol (Oxycholesterol
Oxycholesterol
Oxycholesterol or 5,6-epoxycholestrol is a form of oxidized cholesterol implicated in atherosclerosis. It is commonly formed from the reaction of fats and oxygen during high temperature cooking such as frying. Also see oxysterol....
) in the myelin sheathing of up to 40 neurons. Treatments that lower LDL cholesterols such as (APOE
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
), by mevalonate inhibition are known to impair myelin maintenance in oligodendrocytes, leading to Neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
.
CoQ10 ( Ubiquinone ) Inhibition
Coenzyme Q10 (CoQ10) also known Ubiquinone is an isoprenoid made from mevalonate units and found primarily in the miochondria. It is depleted by inhibiting the supply of mevalonate. This leads to depleted anti-oxidant activity as well as its important role in Electron transfer phosphorylation in the cellular respirationCellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
. Golomb et al. have extensively reviewed and documented the role of statin side effects and very strongly associated them with CoQ10 depletion. A direct causative biochemical link has been in the long term use HMG-CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
and the depletion of the mevalonate required for the biosynthesis of mitochondrial CoQ10.
The correction of this deficiency is discussed in the documentation supporting two US patent applications (Nos.4,933,165 and 4,929,437) for the inclusion of CoQ10 in statin medication both filed in 1990.
A citizen's petition for improved guidance on CoQ10 supplementation was undertaken by a journal of the Life Extension Foundation
Life Extension Foundation
The Life Extension Foundation is a non-profit research-based foundation headquartered in Fort Lauderdale, Florida, established by co-founders Saul Kent and William Faloon in 1980...
in 2002 and remains unresolved.
Mitochondrial Damage, Permanent Neuropathy, Permanent Myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
, Neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
Dolichol Inhibition
DolicholDolichol
Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.-Functions:...
s are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
formation in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
of cells. In this capacity it is critical to the formation of the Glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of dolichols can affect every cellular process in the body.
Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense.
Abnormal phosphorylation of Tau protein
Meske V et al. have shown that when normal phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
is interfered with by mevalonate blockade, our cells increase the production of tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
. Tau is the protein substance of the neurofibrillary tangle
Neurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...
s common to Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and other neurodegenerative diseases
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
.
Abnormal tau phosphorylation and deposition in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and glial cells is one of the major features in tauopathies
Tauopathy
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.The best known of these illnesses is Alzheimer's disease , where tau protein is deposited within neurons in the form of neurofibrillary tangles...
.
The tauopathies are a group of neurodegenerative disorders characterized by the presence of filamentous deposits, consisting of hyperphosphorylated
Hyperphosphorylation
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems or cancer are a likely outcome...
tau protein, in neurons and glia.
Major neurodegenerative tauopathies includes sporadic and hereditary neurodegenerative diseases characterized by filamentous tau deposits in brain and spinal cord.
In prototypical tauopathies, glial and neuronal tau inclusions are the sole or predominant CNS lesions. They include
- amyotrophic lateral sclerosisAmyotrophic lateral sclerosisAmyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
/parkinsonism-dementia complex (ALS-FTDP) - argyrophilic grain dementia
- diffuse neurofibrillary tangles with calcificationCalcificationCalcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Causes:...
- frontotemporal dementiaFrontotemporal dementiaFrontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe...
and parkinsonismParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
linked to chromosome 17 (FTDP-17) - corticobasal degeneration (CBD)
- Pick disease
- Progressive supranuclear palsyProgressive supranuclear palsyProgressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....
(PSP) - Progressive Subcortical GliosisGliosisGliosis is a proliferation of astrocytes in damaged areas of the central nervous system . This proliferation usually leads to the formation of a glial scar....
(PSG) (Subcortical dementia) - Tangle only dementia
Section References:
Alzheimer's and Parkinson Disease 9Th International Conference
Selenoprotein
Only recently have selenoproteins been discovered and the effects of statin use to blockade of the mevalonate pathway on their role in human physiologyHuman physiology
Human physiology is the science of the mechanical, physical, bioelectrical, and biochemical functions of humans in good health, their organs, and the cells of which they are composed. Physiology focuses principally at the level of organs and systems...
are just emerging. Deficiency of selenoproteins has been proven to result in various types of Myopathies formerly seen only in Selenium deficiency
Selenium deficiency
Selenium deficiency is relatively rare in healthy well-nourished individuals. Few cases have been reported.-Causes:It can occur in patients with severely compromised intestinal function, those undergoing total parenteral nutrition, those who have had gastrointestinal bypass surgery, and also on...
- ( a Trace element
Trace element
In analytical chemistry, a trace element is an element in a sample that has an average concentration of less than 100 parts per million measured in atomic count, or less than 100 micrograms per gram....
). Additionally some forms of cognitive dysfunction
Cognitive dysfunction
Cognitive dysfunction is defined as unusually poor mental function, associated with confusion, forgetfulness and difficulty concentrating...
are associated with Selenium deficiency
Selenium deficiency
Selenium deficiency is relatively rare in healthy well-nourished individuals. Few cases have been reported.-Causes:It can occur in patients with severely compromised intestinal function, those undergoing total parenteral nutrition, those who have had gastrointestinal bypass surgery, and also on...
.
Nuclear factor-kappa B NF-κB
The benefit of statin drugs in cardiovascular disease control is in their ability to inhibit this vital transcriptase. The anti-inflammatoryAnti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and immunomodulation effect of statins might be mediated by such statin inhibition of NF-κB. Repoerted improvement in atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
may result from such inhibition of the key inflammatory elements: smooth muscle migration. lymphocyte adhesion, macrophage attraction and platelet activation has been associated with inhibition of NF-κB. The immunodefense system is also keyed to NF-κB, possibly explaining associative connections with changing patterns of certain infections and cancers.
External links
- Collected Videos on Cholesterol and Statins http://www.lizscript.co.uk/Glyn/page6.html
- The Wonder of Cholesterol http://www.lizscript.co.uk/Glyn/page8.html
- Headingley Cafe Scientifique - 6 July 2009 - Long Term Cholesterol Therapy
Meeting Reporthttp://www.lizscript.co.uk/Glyn/index.html Presentation Slideshowhttp://www.lizscript.co.uk/Glyn/page11.html - Duane GravelineDuane GravelineDuane Edgar Graveline is an American physician and former NASA astronaut. He was one of the six scientists selected in 1965, in NASA's fourth group of astronauts, for the Apollo program. He is most famous for being immersed in water for seven days as part of his zero gravity deconditioning...
MD MPH aka Spacedoc http://www.spacedoc.net - Long Term Cholesterol Reducing Therapy a research review