Biosynthesis and biotransformation of cholesterol. Metabolism of ketonå bodies. Regulation and disorders of lipid metabolism
Biological role of cholesterol.
Cholesterol is a lipidic, waxy alcohol found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity. Cholesterol is the principal sterol synthesized by animals, but small quantities are synthesized in other eukaryotes, such as plants and fungi. It is almost completely absent among prokaryotes, which include bacteria. Cholesterol is classified as a sterol (a contraction of steroid and alcohol).
Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as being a precursor for the synthesis of the steroid hormones and bile acids. Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells.
The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries. Although cholesterol is essential for life, high levels in circulation are associated with atherosclerosis. Cholesterol is synthesized in virtually all cells, and significant amounts of it can be absorbed from the diet.
The name cholesterol originates from the Greek
and stereos (solid), and the chemical
-ol for an alcohol, as François Poulletier de
Biological role of cholesterol:
- building blocks of membranes;
- synthesis of steroid hormones;
- synthesis of bile acids;
- synthesis of vitamin D;
- cholesterol is often deposited on the inner walls of blood vessels, together with other lipids, a condition known as atherosclerosis, which often leads to occlusion of blood vessels in the heart and the brain, resulting in heart attacks and strokes, respectively.
liver produces about
and the hydrocarbon chain is embedded in the membrane, alongside the nonpolar fatty acid chains of the other lipids. Some research indicates that cholesterol may act as an antioxidant. Bile, which is stored in the gallbladder and helps digest fats,
is important for the absorption of the fat soluble vitamins, vitamins A, D, E, and K. It is the main precursor of vitamin D and of the steroid hormones, which include cortisol and aldosterone (in the adrenal glands) and progesterone, estrogens, and testosterone (the sex hormones), and their derivatives.
It provides the basic structure of all the steroids. In myelin, it envelopes and insulates nerves, helping greatly to conduct nerve impulses.
Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to protons (positive hydrogen ions) and sodium ions.
Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis. The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane LDL are formed in liver and transport cholesterol from liver to peripheral tissue. LDL is taken up by various tissues and provides cholesterol, which the tissue utilize.
Contents of cholesterol in a blood, transport forms of cholesterol
HDL picks up cholesterol from cell membranes or from other lipoproteins. Cholesterol is converted to cholesterol esters by the lecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or converted to bile salts.
The content of cholesterol in blood plasma – 3-8 mmol/l.
The plasma lipoproteins are complexes in which the lipids and proteins occur in a relatively fixed ratio. They carry water-insoluble lipids between various organs via the blood, in a form with a relatively small and constant particle diameter and weight. Human plasma lipoproteins occur in four major classes that differ in density as well as particle size. They are physically distinguished by their relative rates of flotation in high gravitational fields in the ultracentrifuge.
Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins complex spherical particles which have an exterior composed of amphiphilic proteins and lipids whose outward-facing surface is water-soluble and inward-facing surfaces are lipid-soluble; fats and cholesterol esters are carried internally. There is a large range of lipoproteins within blood, generally called, from larger to smaller size: chylomicrons VLDL is converted to intermediate density lipoproteins (IDL), which is degraded by the liver or converted in blood capillaries to low density lipoproteins LDL by further digestion of triacylglycerols.
very low density lipoprotein (VLDL)
High density lipoproteins (HDL) which is synthesized by the liver, transfers apoproteins to ehylomicrons and VLDL.
HDL picks up cholesterol from cell membranes or from other lipoproteins. Cholesterol is converted to cholesterol esters by the lecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or converted to bile salts.
Composition of the blood lipoproteins
The major components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters, phospholipids, and proteins. Purified proteins (apoproteins) are designated A, B, C, and E.
Component Chylomicrons VLDL IDL LDL HDL
Triacylglycerol 85% 55% 26% 10% 8%
Protein 2% 9% 11% 20% 45%
Type B,C,E B,C,E B,E B A,C,E
Cholesterol 1% 7% 8% 10% 5%
Cholesterol ester 2% 10% 30% 35% 15%
Phospholipid 8% 20% 23% 20% 25%
The cholesterol within all the various lipoproteins is identical although some cholesterol is carried as the "free" alcohol and some is carried as fatty acyl esters referred to as cholesterol esters.
Cholesterol is minimally soluble in water; it can dissolve and travel in the water-based bloodstream only at exceedingly small concentrations. In order to carry large quantities of cholesterol it is transported in the bloodstream by lipoproteins—protein "molecular-suitcases" that are water-dispersible and carry cholesterol and triglycerides as well as phospholipids and cholesterol esters. Phospholipids and cholesterol, being amphipathic, are transported in the surface monolayer of the lipoprotein particle while neutral lipids including triglycerides and cholesterol esters are carried in the core of the lipoprotein particle. By serving as ligands for specific receptors on cell membranes, the apolipoproteins that reside on the surface of a given lipoprotein particle are thought to determine from what cells cholesterol will be removed and to where it will be delivered.
Cholesterol is transported towards peripheral tissues by the lipoproteins chylomicrons, very low density lipoproteins (VLDL) and low-density lipoproteins (LDL). Large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol".
On the other hand, high-density lipoprotein (HDL) particles are thought to transport cholesterol back to the liver for excretion in a process known as reverse cholesterol transport (RCT). Having large numbers of large HDL particles correlates with better health outcomes. In contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.
Metabolism of Chylomicrons
Chylomicrons are synthesized in intestinal epithelial cells. Their triacylglycerols are derived from dietary lipid, and their major apoprotein is apo B-48.Chylomicrons travel through the lymph into the blood. In peripheral tissues, particularly adipose and muscle, the triacylglyerols are digested by lipoprotein lipase.The chylomicron remnants interact with receptors on liver cells and are taken+ up by endocytosis. The contents are degraded by lysosomal enzymes, and the products (amino acids, fatty acids, glycerol, and cholesterol) are released into the cytosol and reutilized.
Metabolism of VLDL
VLDL is synthesized in the liver, particularly after a high-carbohydrate meal. It is formed from triacylglycerols that are package with cholesterol, apoproteins (particularly apo B-100), and phospholipids and it is released into the blood.
In peripheral tissues, particularly adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase, and VLDL is converted to IDL.
IDL returns to the liver, is taken up by endocytosis, and is degraded by lysosomal enzymes.
IDL may also be further degraded by lipoprotein lipase, forming LDL.
LDL reacts with receptors on various cells, is taken up by endocytosis and is digested by lysosomal enzymes.
Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the synthesis of cell memmbranes or bile salts in the liver or steroid hormones in endocrine tissue.
Metabolism of HDL
HDL is synthesized by the liver and released into the blood as disk-shaped particles. The major protein of HDL is apo A.
HDL cholesterol, obtained from cell membranes or from other lipoproteins, is converted to cholesterol esters. As cholesterol esters accumulate in the core of the lipoprotein, HDL particles become spheroids.
HDL particles are taken up by the liver by endocytosis and hydrolyzed by lysosomal enzymes. Cholesterol, released from cholesterol esters may be packaged by the liver in VLDL and released into the blood or converted to bile salts and secreted into the bile.
Stages of biosynthesis of cholesterol, localization of this process
Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day. Cholesterol synthesis occurs in the cytoplasm and microsomes (ER) from the two-carbon acetate group of acetyl-CoA.
The acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation reaction (e.g., fatty acids or pyruvate) in the mitochondria and is transported to the cytoplasm by the same process as that described for fatty acid synthesis (see the Figure below). Acetyl-CoA can also be synthesized from cytosolic acetate derived from cytoplasmic oxidation of ethanol which is initiated by cytoplasmic alcohol dehydrogenase (ADH3). All the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor. The isoprenoid intermediates of cholesterol biosynthesis can be diverted to other synthesis reactions, such as those for dolichol (used in the synthesis of N-linked glycoproteins, coenzyme Q (of the oxidative phosphorylation pathway) or the side chain of heme-a. Additionally, these intermediates are used in the lipid modification of some proteins.
Most of the cholesterol in the body is synthesized therein; some is absorbed in the diet. Cholesterol is more abundant in tissues which either synthesize more, or have more abundant, densely-packed membranes, for example, the liver, spinal cord and brain. It plays a central role in many biochemical processes, such as the building of cell membranes and the synthesis of steroid hormones.
Cholesterol is required in the membranes of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is transported by the bloodstream in low-density or high-density lipoproteins. Low-density lipoproteins are taken into the cell by LDL receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes.Cholesterol is an isoprenoid lipid of the steroid group, esterol subclass, with an important rol in the structure of cell membrane, as a precursor of hormones, Vitamin D and bile acids, and in the pathology of vascular diseases.
Cholesterol biosynthesis occurs in practically all the tissues, but it is more active in liver and in steroid producing organs, like suprarrenal cortex and gonads.
In the Cholesterol synthesis participates enzymes from the smooth endoplasmic reticulum and the cytosol.
Pathway for the movement of acetyl-CoA units from within the mitochondrion to the cytoplasm for use in lipid and cholesterol biosynthesis. Note that the cytoplasmic malic enzyme catalyzed reaction generates NADPH which can be used for reductive biosynthetic reactions such as those of fatty acid and cholesterol synthesis.
The process of cholesterol synthesis has five major steps:
1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA is converted to mevalonate
3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2
4. IPP is converted to squalene
5. Squalene is converted to cholesterol.
Pathway of cholesterol biosynthesis.
Synthesis begins with the transport of acetyl-CoA from the mitochondrion to the cytosol. The rate limiting step occurs at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation reactions are required to solubilize the isoprenoid intermediates in the pathway. Intermediates in the pathway are used for the synthesis of prenylated proteins, dolichol, coenzyme Q and the side chain of heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands for pyrophosphate. Place mouse over intermediate names to see structure.
Acetyl-CoA units are converted to mevalonate by a series of reactions that begins with the formation of HMG-CoA. Unlike the HMG-CoA formed during ketone body synthesis in the mitochondria, this form is synthesized in the cytoplasm. However, the pathway and the necessary enzymes are similar to those in the mitochondria. Two moles of acetyl-CoA are condensed in a reversal of the thiolase reaction, forming acetoacetyl-CoA. The cytoplasmic thiolase enzyme involved in cholesterol biosynthesis is acetoacetyl-CoA thiolase encoded by the ACAT2 gene. Although the bulk of acetoacetyl-CoA is derived via this process, it is possible for some acetoacetate, generated during ketogenesis, to diffuse out of the mitochondria and be converted to acetoacetyl-CoA in the cytosol via the action of acetoacetyl-CoA synthetase (AACS). Acetoacetyl-CoA and a third mole of acetyl-CoA are converted to HMG-CoA by the action of HMG-CoA synthase.
HMG-CoA is converted to mevalonate by HMG-CoA reductase, HMGR (this enzyme is bound in the endoplasmic reticulum, ER). HMGR absolutely requires NADPH as a cofactor and two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate. The reaction catalyzed by HMGR is the rate limiting step of cholesterol biosynthesis, and this enzyme is subject to complex regulatory controls as discussed below.
Mevalonate is then activated by two successive phosphorylations (catalyzed by mevalonate kinase, and phosphomevalonate kinase), yielding 5-pyrophosphomevalonate. In humans, mevalonate kinase resides in the cytosol indicating that not all the reactions of cholesterol synthesis are catalyzed by membrane-associated enzymes as originally described. After phosphorylation, an ATP-dependent decarboxylation yields isopentenyl pyrophosphate, IPP, an activated isoprenoid molecule. Isopentenyl pyrophosphate is in equilibrium with its isomer, dimethylallyl pyrophosphate, DMPP. One molecule of IPP condenses with one molecule of DMPP to generate geranyl pyrophosphate, GPP. GPP further condenses with another IPP molecule to yield farnesyl pyrophosphate, FPP. Finally, the NADPH-requiring enzyme, squalene synthase catalyzes the head-to-tail condensation of two molecules of FPP, yielding squalene. Like HMGR, squalene synthase is tightly associated with the ER. Squalene undergoes a two step cyclization to yield lanosterol. The first reaction is catalyzed by squalene monooxygenase. This enzyme uses NADPH as a cofactor to introduce molecular oxygen as an epoxide at the 2,3 position of squalene. Through a series of 19 additional reactions, lanosterol is converted to cholesterol.
The terminal reaction in cholesterol biosynthesis is catalyzed by the enzyme 7-dehydrocholesterol reductase encoded by the DHCR7 gene. Functional DHCR7 protein is a 55.5 kDa NADPH-requiring integral membrane protein localized to the microsomal membrane. Deficiency in DHCR7 (due to gene mutations) results in the disorder called Smith-Lemli-Opitz syndrome, SLOS. SLOS is characterized by increased levels of 7-dehydrocholesterol and reduced levels (15% to 27% of normal) of cholesterol resulting in multiple developmental malformations and behavioral problems.
The main “materials” required for the synthesis of cholesterol are:
a) Acetyl CoA, whose acetyl groups provide all the carbons of cholesterol.
b) ATP, as an energy source.
c) NADPH.H+ as provider of the reduction equivalents required for the synthesis.
There are three stage in cholesterol synthesis. (1) acetic acid is converted to mevalonic acid, (2) mevalonic acid is converted into squalene, and (3) squalene is converted into cholesterol.
I.- Mevalonate synthesis
Mevalonic acid is formed by condensation of three molecules of acetyl-CoA. The key intermediate in this process is b-hydroxy-b-methylglutaryl-CoA (HMG-CoA), which is formed as follows:
Acetyl-CoA Acetyl-CoA Acetoacetyl-CoA
The enzyme is called b-hydroxy-b-methylglutaryl-CoA synthase.
The b-hydroxy-b-methylglutaryl-CoA undergoes an irreversible two-step reduction of one of its carboxyl groups to an alcohol group, with concomitant loss of CoA, by the action of hydroxymethylglutaryl-CoA reductase, to yield mevalonate:
Mevalonate is phosphorylated by ATP, first to the 5-monophosphate ester and then to the 5-pyrophosphomevalonic acid:
A third phosphorylation, at carbon atom 3, yields a very unstable intermediate which loses phosphoric acid and decarboxylates to form 3-isopentenyl pyrophosphate, which isomerizes to 3,3-dimethylallyl pyrophosphate.
Normal healthy adults synthesize cholesterol at a rate of approximately 1g/day and consume approximately 0.3g/day. A relatively constant level of cholesterol in the blood (150–200 mg/dL) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilized in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis.
The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free cholesterol through the activity of acyl-CoA:cholesterol acyltransferase, ACAT
3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse transport.
Regulation of HMGR activity is the primary means for controlling the level of cholesterol biosynthesis. The enzyme is controlled by four distinct mechanisms: feed-back inhibition, control of gene expression, rate of enzyme degradation and phosphorylation-dephosphorylation.
The first three control mechanisms are exerted by cholesterol itself. Cholesterol acts as a feed-back inhibitor of pre-existing HMGR as well as inducing rapid degradation of the enzyme. The latter is the result of cholesterol-induced polyubiquitination of HMGR and its degradation in the proteosome (see proteolytic degradation below). This ability of cholesterol is a consequence of the sterol sensing domain, SSD of HMGR. In addition, when cholesterol is in excess the amount of mRNA for HMGR is reduced as a result of decreased expression of the gene. The mechanism by which cholesterol (and other sterols) affect the transcription of the HMGR gene is described below under regulation of sterol content.
Regulation of HMGR through covalent modification occurs as a result of phosphorylation and dephosphorylation. The enzyme is most active in its unmodified form. Phosphorylation of the enzyme decreases its activity. HMGR is phosphorylated by AMP-activated protein kinase, AMPK (this is not the same as cAMP-dependent protein kinase, PKA). AMPK itself is activated via phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2 enzymes. The primary kinase sensitive to rising AMP levels is LKB1. LKB1 was first identified as a gene in humans carrying an autosomal dominant mutation in Peutz-Jeghers syndrome, PJS. LKB1 is also found mutated in lung adenocarcinomas. The second AMPK phosphorylating enzyme is calmodulin-dependent protein kinase kinase-beta (CaMKKβ). CaMKKβ induces phosphorylation of AMPK in response to increases in intracellular Ca2+ as a result of muscle contraction. Visit AMPK: The Master Metabolic Regulator for more detailed information on the role of AMPK in regulating metabolism.
Regulation of HMGR by covalent modification. HMGR is most active in the dephosphorylated state. Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK, (used to be termed HMGR kinase), an enzyme whose activity is also regulated by phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2 enzymes: LKB1 and CaMKKβ. Hormones such as glucagon and epinephrine negatively affect cholesterol biosynthesis by increasing the activity of the inhibitor of phosphoprotein phosphatase inhibitor-1, PPI-1. Conversely, insulin stimulates the removal of phosphates and, thereby, activates HMGR activity. Additional regulation of HMGR occurs through an inhibition of its' activity as well as of its' synthesis by elevation in intracellular cholesterol levels. This latter phenomenon involves the transcription factor SREBP described below.
The activity of HMGR is additionally controlled by the cAMP signaling
pathway. Increases in cAMP lead to activation of cAMP-dependent protein kinase,
PKA. In the context of HMGR regulation, PKA phosphorylates phosphoprotein
phosphatase inhibitor-1 (PPI-1) leading to an increase in its' activity. PPI-1
can inhibit the activity of numerous phosphatases including protein phosphatase
Since the intracellular level of cAMP is regulated by hormonal stimuli, regulation of cholesterol biosynthesis is hormonally controlled. Insulin leads to a decrease in cAMP, which in turn activates cholesterol synthesis. Alternatively, glucagon and epinephrine, which increase the level of cAMP, inhibit cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to inhibit, HMGR activity is consistent with the effects of these hormones on other metabolic pathways. The basic function of these two hormones is to control the availability and delivery of energy to all cells of the body.
Long-term control of HMGR activity is exerted primarily through control over the synthesis and degradation of the enzyme. When levels of cholesterol are high, the level of expression of the HMGR gene is reduced. Conversely, reduced levels of cholesterol activate expression of the gene. Insulin also brings about long-term regulation of cholesterol metabolism by increasing the level of HMGR synthesis.
The stability of HMGR is regulated as the rate of flux through the mevalonate synthesis pathway changes. When the flux is high the rate of HMGR degradation is also high. When the flux is low, degradation of HMGR decreases. This phenomenon can easily be observed in the presence of the statin drugs as discussed below.
HMGR is localized to the ER and like SREBP (see below) contains a sterol-sensing domain, SSD. When sterol levels increase in cells there is a concomitant increase in the rate of HMGR degradation. The degradation of HMGR occurs within the proteosome, a multiprotein complex dedicated to protein degradation. The primary signal directing proteins to the proteosome is ubiquitination. Ubiquitin is a 7.6kDa protein that is covalently attached to proteins targeted for degradation by ubiquitin ligases. These enzymes attach multiple copies of ubiquitin allowing for recognition by the proteosome. HMGR has been shown to be ubiquitinated prior to its degradation. The primary sterol regulating HMGR degradation is cholesterol itself. As the levels of free cholesterol increase in cells, the rate of HMGR degradation increases.
Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins. Dietary cholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDLs. The liver synthesizes VLDLs and these are converted to LDLs through the action of endothelial cell-associated lipoprotein lipase. Cholesterol found in plasma membranes can be extracted by HDLs and esterified by the HDL-associated enzyme LCAT. The cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and LDLs via the action of cholesteryl ester transfer protein (apo-D) which is associated with HDLs. Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver in LDLs. Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver.
Cholesterol is oxidized by the liver into a variety of bile acids. These in turn are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and non-conjugated bile acids along with cholesterol itself is excreted from the liver into the bile. Approximately 95% of the bile acids are reabsorbed from the intestines and the remainder lost in the feces. The excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation which is essential for the digestion and absorption of dietary fats. Under certain circumstances, when more concentrated, as in the gallbladder, cholesterol crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.
Cytochrome P450 enzymes are involved in a diverse array of biological processes that includes lipid, cholesterol, and steroid metabolism as well as the metabolism of xenobiotics. The now common nomenclature used to designate P450 enzymes is CYP. There are at least 57 CYP enzymes in human tissues with eight being involved in cholesterol biosynthesis and metabolism, which includes conversion of cholesterol to bile acids. CYP metabolism of cholesterol yields several oxysterols that function as biologically active molecules such as in the activation of the liver X receptors (LXRs) and SREBP (see the next section).
CYP3A4: CYP3A4 is also known as glucocorticoid-inducible P450 and nifedipine oxidase. Nifedipine is a member of the calcium channel blocker drugs used to treat hypertension. CYP3A4 is a major hepatic P450 enzyme and is responsible for the biotransformation of nearly 60% of all commercially available drugs. With respect to cholesterol metabolism, CYP3A4 catabolizes cholesterol to 4β-hydroxycholesterol. This cholesterol derivative is one of the major circulating oxysterols and is seen at elevated levels in patients treated with anti-seizure medications such as carbamazepine, phenobarbitol, and phenytoin. The nuclear receptor, pregnane X receptor (PXR), is known to be an inducer of the CYP3A4 gene.
CYP7A1: CYP7A1 is also known as cholesterol 7α-hydroxylase and is the rate limiting enzyme in the primary pathway of bile acid synthesis referred to as the classic pathway. This reaction of bile acid synthesis plays a major role in hepatic regulation of overall cholesterol balance. Deficiency in CYP7A1 manifests with markedly elevated total cholesterol as well as LDL, premature gallstones, premature coronary and peripheral vascular disease. Treatment of this disorder with members of the statin drug family do not alleviated the elevated serum cholesterol due to the defect in hepatic diversion of cholesterol into bile acids.
CYP7B1: CYP7B1 is also known as oxysterol 7α-hydroxylase and is involved in the synthesis of bile acids via the less active secondary pathway referred to as the acidic pathway. A small percentage (1%) of individuals suffering from autosomal recessive hereditary spastic paraplegia 5A (SPG5A) have been shown to harbor mutations in the CYP7B1 gene.
CYP8B1: CYP8B1 is also known as sterol 12a-hydroxylase and is involved in the conversion of 7-hydroxycholesterol (CYP7A1 product) to cholic acid which is one of two primary bile acids and is derived from the classic pathway of bile acid synthesis. The activity of CYP8B1 controls the ratio of cholic acid over chenodeoxycholic acid in the bile.
CYP27A1: CYP27A1 is also known as sterol 27-hydroxylase and is localized to the mitochondria. CYP27A1 functions with two cofactor proteins called adrenodoxin and adrenodoxin reductase to hydroxylate a variety of sterols at the 27 position. CYP27A1 is also involved in the diversion of cholesterol into bile acids via the less active secondary pathway referred to as the acidic pathway. Deficiencies in CYP27A1 result in progressive neurological dysfunction, neonatal cholestasis, bilateral cataracts, and chronic diarrhea.
CYP39A1: CYP39A1 is also known as oxysterol 7α-hydroxylase 2. This P450 enzyme was originally identified in mice in which the CYP7B1 gene had been knocked out. The preferential substrate for CYP39A1 is 24-hydroxycholesterol, which is a major product of CYP46A1, which via CYP39A1 action is diverted into bile acid synthesis.
CYP46A1: CYP46A1 is also known as cholesterol 24-hydroxylase. This enzyme is expressed primarily in neurons of the central nervous system where it plays an important role in metabolism of cholesterol in the brain. The product of CYP46A1 action if 24S-hydroxycholesterol which can readily traverse the blood-brain-barrier to enter the systemic circulation. This pathway of cholesterol metabolism in the brain is a part of the reverse cholesterol transport process and serves as a major route of cholesterol turnover in the brain. 24S-hydroxycholesterol is a known potent activator of LXR and as such serves as an activator of the expression of LXR target genes and thus, can effect regulation of overall cholesterol metabolism not only in the brain but many other tissues as well.
CYP51A1: CYP51A1 is also referred to as lanosterol-14α-demethylase. This P450 enzyme is the only one of the eight that is involved in de novo cholesterol biosynthesis and it catalyzes the removal of the 14α-methyl group from lanosterol resulting in the generation of at least two oxysterols that, in mammalian tissues, are efficiently converted into cholesterol as well as more polar sterols and steryl esters. The oxysterols derived through the action of CYP51A1 inhibit HMGR and are also known to inhibit sterol synthesis. Knock-out of the mouse CYP51A1 homolog results in a phenotype similar to that seen in the human disorder known as Antley-Bixler syndrome (ABS). ABS represents a group of heterogeneous disorders characterized by skeletal, cardiac, and urogenital abnormalities that have frequently been associated with mutations in the fibroblast growth factor receptor 2 (FGFR2) gene.
Nutrition and health
Lipids play diverse and important roles in nutrition and health. Many lipids are absolutely essential for life, however, there is also considerable awareness that abnormal levels of certain lipids, particularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our bodies and in our diet. Animals in general use fat for energy storage because fat stores 9 KCal/g of energy.
Plants, which don’t move around, can afford to store food for energy in a less compact but more easily accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat stores over twice as much energy/gram as other sources of energy.
We need fats in our bodies and in our diet. Animals in general use fat for energy storage because fat stores 9 KCal/g of energy. Plants, which don’t move around, can afford to store food for energy in a less compact but more easily accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat stores over twice as much energy/gram as fat. By the way, this is also related to the idea behind some of the high-carbohydrate weight loss diets.
The human body burns carbohydrates and fats for fuel in a given proportion to each other. The theory behind these diets is that if they supply carbohydrates but not fats, then it is hoped that the fat needed to balance with the sugar will be taken from the dieter’s body stores. Fat is also is used in our bodies to a) cushion vital organs like the kidneys and b) serve as insulation, especially just beneath the skin.
Able to control
What you eat.Certain foods have types of fat that raise your cholesterol level.
· Saturated fat raises your low-density lipoprotein (LDL) cholesterol level more than anything else in your diet
· Trans fatty acids (transfats) are made when vegetable oil is hydrogenated to harden it. Transfatty acids raise cholesterol levels
· Cholesterol is found in foods that come from animal sources, for example, egg yolks, meat, and cheese
Weight. Being overweight tends to increase your LDL level, lower your high-density lipoprotein (HDL) level, and increase your total cholesterol level.
Activity level.Lack of regular exercise can lead to weight gain, which could raise your LDL cholesterol level. Regular exercise can help you lose weight and lower your LDL level. It can also help you raise your HDL level.
Unable to control.
Heredity.High blood cholesterol can run in families. An inherited genetic condition (familial hypercholesterolemia) results in very high LDL cholesterol levels. It begins at birth, and may result in a heart attack at an early age.
Age. Starting at puberty, men have lower levels of HDL than women. As women and men get older, their LDL cholesterol levels rise. Younger women have lower LDL cholesterol levels than men, but after age 55, women have higher levels than men.
A thorough examination of the state of the live blood allows the doctor to consider various nutritional factors that often prove to be the underlying causes of chronic ill-health. Furthermore, the patient's physical response to a recommended course of treatment can be monitored visually. Improvements in the condition of the blood can be seen, sometimes within a few days and usually within weeks. This gives patients tremendous encouragement to continue with their regimen of supplementation and diet.
The importance of obesity, a sedentary lifestyle, very high fat diet, and intake of large concentrations of refined carbohydrates should not be underestimated as causes of severe hypertriglyceridemia. Instituting a program of progressive aerobic and toning exercise, weight loss, and dietary management can significantly lower triglyceride levels and, in some cases, normalize them.
During pregnancy, severe hypertriglyceridemia is an unusual complication and may cause pancreatitis.
· Many case reports have been published describing interventions to manage this condition.
· Most commonly, a very low-fat diet was sufficient to control triglycerides and prevent pancreatitis.
· Intermittent and, in persistent cases, continuous total parenteral nutrition has been used—usually in the third trimester.
To treat hyperlipidemia, a diet low in total fat, saturated fat, and cholesterol is recommended, along with reducing or avoiding alcohol intake. The American Heart Association (AHA) endorses the following dietary recommendations for people with high blood cholesterol:
· Total fat: 25% of total calories
· Saturated fat: less than 7% total calories
· Polyunsaturated fat: up to 10% total calories
· Monounsaturated fat: up to 20% total calories
· Carbohydrates: 50-60% total calories
· Protein: ~15% total calories
· Cholesterol: less than 200 mg/dL
· Soluble fiber such as psyllium: 10- 25g
Categories of appropriate foods include:
· Lean meat/fish: less than 5 oz/day
· Eggs: less than 2 yolks per week (whites unlimited)
· Low fat dairy products (<1% fat): 2-3 servings/day
· Grains, especially whole grains: 6-8 tsp/day
· Vegetables: less than 6 servings per day
· Fruits: 2-5 servings per day
These recommendations translate into the following practical dietary guidelines:
· Select only the leanest meats, poultry, fish and shellfish. Choose chicken and turkey without skin or remove skin before eating. Some fish, like cod, have less saturated fat than either chicken or meat.
· Limit goose and duck. They are high in saturated fat, even with the skin removed.
· Some chicken and turkey hot dogs are lower in saturated fat and total fat than pork and beef hot dogs. There are also lean beef hot dogs and vegetarian (tofu) franks that are low in fat and saturated fat.
· Dry peas, beans and tofu can be used as meat substitutes that are low in saturated fat and cholesterol. Dry peas and beans also have a lot of fiber, which can help to lower blood cholesterol.
· Egg yolks are high in dietary cholesterol. A yolk contains about 213 mg. They should be limited to no more than 2 per week, including the egg yolks in baked goods and processed foods. Egg whites have no cholesterol, and can be substituted for whole eggs in recipes.
· Like high fat meats, regular dairy foods that contain fat, such as whole milk, cheese, and ice cream, are also high in saturated fat and cholesterol. However, dairy products are an important source of nutrients and the diet should include 2 to 3 servings per day of low-fat or nonfat dairy products.
· When shopping for hard cheeses, select them fat-free, reduced fat, or part skim.
· Select frozen desserts that are lower in saturated fat, such as ice milk, low-fat frozen yogurt, low-fat frozen dairy desserts, sorbets, and popsicles.
· Saturated fats should be replaced with unsaturated fats. Select liquid vegetable oils that are high in unsaturated fats, such as canola, corn, olive, peanut, saf-flower, sesame, soybean, and sunflower oils.
· Limit butter, lard, and solid shortenings. They are high in saturated fat and cholesterol.
· Select light or nonfat mayonnaise and salad dressings.
· Fruits and vegetables are very low in saturated fat and total fat, and have no cholesterol. Fruits and vegetables should be eaten as snacks, desserts, salads, side dishes, and main dishes.
· Breads, cereals, rice, pasta, grains, dry beans, and peas are high in starch and fiber and low in saturated fat and calories. They also have no dietary cholesterol, except for some bakery breads and sweet bread products made with high fat, high cholesterol milk, butter and eggs.
· Select whole grain breads and rolls whenever possible. They have more fiber than white breads.
· Most dry cereals are low in fat. Limit high-fat granola, muesli, and cereal products made with coconut oil and nuts, which increases the saturated fat content.
· Limit sweet baked goods that are made with saturated fat from butter, eggs, and whole milk such as croissants, pastries, muffins, biscuits, butter rolls, and doughnuts.
· Snacks such as cheese crackers, and some chips are often high in saturated fat and cholesterol. Select rather low-fat ones such as bagels, bread sticks, cereals without added sugar, frozen grapes or banana slices, dried fruit, non-oil baked tortilla chips, popcorn or pretzels.
Reductions in circulating cholesterol levels can have profound positive impacts on cardiovascular disease, particularly on atherosclerosis, as well as other metabolic disruptions of the vasculature. Control of dietary intake is one of the easiest and least cost intensive means to achieve reductions in cholesterol. Recent studies in laboratory rats has demonstrated an additional benefit of reductions in dietary cholesterol intake. In these animals it was observed that reductions in dietary cholesterol not only resulted in decreased serum VLDLs and LDLs, and increased HDLs but DNA synthesis was also shown to be increased in the thymus and spleen. Upon histological examination of the spleen, thymus and lymph nodes it was found that there was an increased number of immature cells and enhanced mitotic activity indicative of enhanced proliferation. These results suggest that a marked reduction in serum LDLs, induced by reduced cholesterol intake, stimulates enhanced DNA synthesis and cell proliferation.
Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of athersclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if non-pharmacologic interventions (altered diet and exercise) have failed to lower plasma lipids.
Nicotinic acid: Nicotinic acid reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL secretion, as well as suppressing the flux of FFA release from adipose tissue by inhibiting lipolysis. In addition, nicotinic administration strongly increases the circulating levels of HDLs. Patient compliance with nicotinic acid administration is sometimes compromised because of the unpleasant side-effect of flushing (strong cutaneous vasodilation). Recent evidence has shown that nicotinic acid binds to and activates the G-protein coupled receptor identified as GPR109A (also called HM74A or PUMA-G). The identity of a receptor to which nicotinic acid binds allows for the development of new drug therapies that activate the same receptor but that may lack the negative side-effect of flushing associated with nicotinic acid. Because of its ability to cause large reductions in circulating levels of cholesterol, nicotinic acid is used to treat Type II, III, IV and V hyperlipoproteinemias.
Representatives of ketone bodies, place and mechanism of ketogenesis.
Fatty acids can be used as the major fuel for tissues such as muscle, but they cannot cross the blood-brain barrier, and thus cannot be used by the central nervous system (CNS). This becomes a major problem during starvation (fasting), particularly for organisms such as ourselves in which CNS metabolism constitute a major portion of the resting basal metabolic rate. These organism must provide glucose to the CNS to provide for metabolic needs, and thus during the initial fasting period must break down substantial amounts of muscle tissue (protein) to provide the amino acid precursors of gluconeogenesis. Obviously the organism could not survive long under such a regime. What is needed is an alternate fuel source based on fat rather than muscle. The so-called ketone bodies serve this function:
Note that only two of the ketone bodies are in fact ketones, and that acetone is an "unintentional" breakdown product resulting from the instability of acetoacetate at body temperature. Acetone is not available as fuel to any significant extent, and is thus a waste product.
CNS tissues can use ketone bodies any time, the
problem is the normally very low concentrations (<
The limiting factor in using ketone
bodies then becomes the ability of the liver to synthesis them, which requires
the induction of the enzymes required for acetoacetate biosynthesis. Normal
glucose concentrations inhibit ketone body synthesis, thus the ketone bodies
will only begin to be synthesized in high concentrations as serum glucose
concentrations fall. As an example, ketone bodies might start at about
Ketogenesis occurs in the mitochondrial matrix in liver mitochondria. Fatty acids are first broken down to acetyl CoA via beta-oxidation (providing energy for liver metabolism from the reducing equivalents generated). The acetyl CoA is then used in ketogenesis:
Mechanisms of the using of ketone bodies in tissues with the purpose of energy obtsining (ketolysis).
The ketone bodies are water soluble and are transported across the inner mitochondrial membrane as well as across the blood-brain barrier and cell membranes. Thus they can be used as a fuel source by a variety of tissues including the CNS. They are preferred substrates for aerobic muscle and heart, thus sparing glucose when they are available.
In the peripheral tissues the ketones must be reconverted to acetyl CoA in the mitochondria:
The mechanism of the increase of ketone bodies content in blood at diabetus mellitus and starvation
When the body is deprived of food whether by voluntary or involuntary fasting, starvation is the net result. During starvation, glycogen reserves are rapidly depleted and the body begins to metabolize reserves of fat and protein.
The entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetic acid for the formation of citric acid. In starvation or uncontrolled diabetes situations, oxaloacetic acid is used to synthesize glucose and is then not available for use with acetyl CoA. Under these conditions, acetyl CoA is diverted from the citric acid cycle to the formation of acetoacetic and 3-hydroxybutanoic acids.
The odor of acetone may be detected on the breath of a person with excess ketone bodies in the blood. The overall accumulation of ketone bodies in blood and urine is known as ketosis. The acids also upset buffers in the blood to cause acidosis.
Both acetoacetic acid and 3-hydroxybutanoic acid can be used by the heart, kidneys, and brain for metabolism to produce energy. The heart and kidneys actually prefer these to glucose. In contrast, the brain prefers glucose, but will adapt if necessary in starvation or diabetic conditions.
Ketonuria is a medical condition in which ketone bodies are present in the urine.
It is seen in conditions wherein the body produces excess ketones as an alternative source of energy. It is seen during starvation or more commonly in type I diabetes mellitus. Production of ketone bodies is a normal response to a shortage of glucose, meant to provide an alternate source of fuel from fatty acids.
After 24 hrs fasting, ketone body levels increase in blood (called ketonemia or ketosis but all of it used up by the muscles no ketone bodies are left to be excreted in urine.
Screening for ketonuria is done frequently for acutely ill patients, presurgical
patients, and pregnant women. Any diabetic patient who has elevated levels of
blood and urine glucose should be tested for urinary ketones. In addition, when
diabetic treatment is being switched from insulin to oral hypoglycemic agents,
the patient's urine should be monitored for ketonuria. The development of
ketonuria within 24 hours after insulin withdrawal usually indicates a poor
response to the oral hypoglycemic agents. Diabetic patients who use oral
hypoglycemic agents should have their urine tested regularly for glucose and
ketones because oral hypoglycemic agents, unlike insulin, do not control
diabetes when an acute infection or other illness develops.
In conditions associated with acidosis, urinary ketones are tested to assess the severity of acidosis and to monitor treatment response. Urine ketones appear before there is any significant increase in blood ketones; therefore, urine ketone measurement is especially helpful in emergency situations. During pregnancy, early detection of ketonuria is essential because ketoacidosis is a factor associated with intrauterine death.
In nondiabetic persons, ketonuria may occur during acute illness or severe stress. Approximately 15% of hospitalized patients may have ketonuria, even though they do not have diabetes. In a diabetic patient, ketone bodies in the urine suggest that the patient is not adequately controlled and that adjustments of medication, diet, or both should be made promptly. In the nondiabetic patient, ketonuria reflects a reduced carbohydrate metabolism and excessive fat metabolism.
II. Regulation and disorders of lipids metabolism.
Regulation of lipid metabolism. Role of hormones and vitamins in lipolysis and lipogenesis.
Lipolysis is the breakdown of fat stored in fat cells. During this process, free fatty acids are released into the bloodstream and circulate throughout the body. Ketones are produced, and are found in large quantities in ketosis (a state in metabolism occurring when the liver converts fat into fatty acids and ketone bodies which can be used by the body for energy.). Lipolysis testing strips such as Ketostix are used to recognize ketosis.
The following hormones induce lipolysis: epinephrine, norepinephrine, glucagon and adrenocorticotropic hormone. These trigger 7TM receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue.
Triglycerides undergo lipolysis (hydrolysis by lipases) and are broken down into glycerol and fatty acids. Once released into the blood, the relatively hydrophobic free fatty acids bind to serum albumin for transport to tissues that require energy. The glycerol also enters the bloodstream and is absorbed by the liver or kidney where it is converted to glycerol 3-phosphate by the enzyme glycerol kinase. Hepatic glycerol 3-phosphate is mostly converted into dihydroxyacetonephosphate (DHAP) and then glyceraldehyde 3-phosphate (G3P) to rejoin the glycolysis and gluconeogenesis pathway.
Pathologies of lipids metabolism:
Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is a risk factor for certain health conditions or increased mortality. Obesity develops from the interaction of individual biology and the environment. Excessive body weight has been shown to predispose to various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, sleep apnea, and osteoarthritis. Obesity is both an individual clinical condition and is increasingly viewed as a serious public health problem.
People that are overweight can cause a lot of strain on the heart. The extra weight forces the heart to work harder, making it less effective at pumping out blood to through the arteries. In addition, too much weight can lead to an increase in blood pressure and blood cholesterol, and create a higher risk of diabetes. A carefully regulated diet with a limited amount of fat and alcohol intake along with a regular exercise regimen can help with weight loss.
Fatty degeneration of liver
It is a recognized fact that all-seed diets, which are not only high in fat, but deficient in many essential nutrients, predispose psittacine birds to fatty liver degeneration. It would seem that the prevalence of this condition in all companion birds, including cockatiels, would be decreasing since the advent of pelleted diets, but this does not appear to be happening. Is this because we cockatiel breeders do not recognize this condition when it appears and kills our birds? Is it because we don’t know enough about what causes the disease? Is it because we don’t generally recognize the benefits of pellets? Is it because, in our pursuit of "substance" in show birds, we don’t differentiate between a bird with a large frame and one that is fat?
The main symptom that brought the problem to my attention was a substantial decline in weight, although I did not notice a change in eating habits. As all my birds are kept in large flights when not breeding, I did not notice this until I removed the birds from the flight in order to set them up for breeding. (Foods present in the flight cages are: pellets at all times, seed three times a week, and cooked grain and vegetable "soft food" 3 times a week.) At that time, their weight loss led me to take them to the doctor, where blood tests revealed liver problems. Although I did medicate both birds, and tried very hard to get them to eat a healthier diet in order to possibly reverse the course of this disease, they both died within two months of diagnosis. Necropsy did confirm the cause of death as fatty degeneration and failure of the liver.
According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia), or, more correctly, higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles, LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to colloquially as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices and other factors.
Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease.
In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.
Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration. Recently, a post-hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol".
Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, but some studies suggest a link with depression, cancer and cerebral hemorrhage. Generally, the low cholesterol levels seem to be a consequence of an underlying illness, rather than a cause.
Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the liquid crystalline cholesteric phase. The cholesteric phase is in fact a chiral nematic phase, and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used in liquid crystal thermometers and temperature-sensitive paints.
When carbohydrates enter the body, they are broken down into glucose (sugar), which is absorbed into the blood. Upon absorption, the pancreas secretes the hormone insulin, which allows the glucose to be absorbed into the body’s tissues and cells. Diabetes results when the body is unable to produce sufficient amounts of insulin or does not respond to the insulin produced.
As a result, there is a glucose buildup in the body. This buildup can cause an increase in high blood pressure, high levels of LDL cholesterol, and obesity, which all contribute to cardiovascular disease. A controlled diet, regular exercise, and blood glucose testing, as well as oral medication and insulin injections can help patients with diabetes.
Free radicals are molecular species which contain an unpaired electron (usually represented as R·). Consequently, they are some of the most chemically reactive molecules known. Because of the need to pair its single electron, a free radical must abstract a second electron from a neighbouring molecule. This causes the formation of yet another free radical and self-propagating chain reaction ensues.
Free radicals in human body can arise from fatty food, smoking, alcohol, environmental pollutants, hydrogen peroxide, pollutants, ozone, toxins, carcinogen toxins, ionisation etc. The vast majority of free radicals come from within the body, an unavoidable by-product of living system. Free radical intermediates are produced in living systems under normal conditions, the body handles free radicals formed by the breakdown of compounds through the process of metabolism. The major sources of free radicals (such as O2- and HO2·) are modest leakages from the electron transport chains of mitochondria, chloroplasts and endoplasmic reticulum.
The resulting free radicals, such as superoxide anion (O2-) and hydroxyl radical (OH·), as well as the non-radical hydrogen peroxide, can damage macromolecules, including DNA, proteins and lipids. Likewise, other products of oxygen metabolism, such as hypochlorous acid, chloramines, and oxidised lipids have all been related in such damages. The superoxide radical, although it is unreactive in comparison with many other radicals, biological systems can convert it into other more reactive species, such as peroxyl (ROO·), alkoxyl (RO·) and hydroxyl (HO·) radicals.
There are four types of free radicals damages:
1. Damage to fat compounds: The fatty membranes surrounding the cells being the prime target to free radicals attacks. The damaged membranes then loose its ability to transport oxygen, nutrients or water to the cells.
2. Damage to protein molecules: Free radicals also attack the nucleic acid which comprise the genetic code within each cell. The nucleic acids function is to regulate the normal cell function, growth and also to repair the damaged tissues.
3. Cell damage: Damages done to the chromosoins and nucleic acids might initiate the growth of abnormal cells, which is the first step in cancer development.
4. Lysosomes damages: Lysosomes are little sacs in the cell that contain degenerative enzymes. The enzymes leak out when the membrane cell breaks and they start digesting the cell itself, spreading to nearby cell causing a chain reaction of destruction which, eventually, will lower the immune system resistance.
And such production of reactive oxygen species and other free radicals and theirs damages to various molecules and cells may result not only in the toxicity of xenobiotics but also in the pathophysiology of ageing, and various age-related diseases, including cataracts, arteriosclerosis, neoplastic diseases, diabetes, chronic inflammatory diseases, cancer and etc.
Fortunately, the body also has several natural chemical means or systems for neutralizing free radicals. There is agents that counteract and minimize free radical damage and their function is to donate or provide unpaired electrons to which free radicals can attach without causing harm. Such "cell-savers" are called "Antioxidants."
Antioxidants get their name because they combat oxidation. Oxidation is a reaction in which a molecule looses an electron. The two major sources of antioxidants are:
1. Those that you get from food or food supplements
2. Those produced within your own body.
And there are some types of antioxidants, like the Flavonoids, found in the skin and seeds of fruits, possess the ability to physically capture free radicals until these are actually removed from the body. Others, like Sulphorophane, found in broccoli, tend to enhance the body’s own free radical scavenging mechanism. And finally, the ones like L. Limonene, phytochemical found in citrus fruit peels, can actually perform both actions. Some popular antioxidants today include Vitamin E, Vitamin C, Vitamin A, which can be taken under a health supplement form or through fruits, vegetables, fish oil, green tea, sesame oil, and Genistein from soy bean shown to be cancer preventive. Some antioxidants come from minerals, such as selenium, copper, zinc (they are considered antioxidants because they work together in conjunction with an antioxidant enzyme and are necessary for the enzyme to function properly).. etc. The list of dietary antioxidants goes on and on, and scientist are continually discovering more.
Free radicals, such as superoxide, hydroxyl ions and nitric oxide all contain an unpaired electron. These radicals can have a negative effect on cells causing oxidative damage that leads to cell death.
Antioxidants, such as vitamin E, prevent cell damage by binding to the free radical and neutralising its unpaired electron. For example, vitamin E binds to OO· or O2· they form an intermediate structure that is converted to a-tocopherylquinone. A recent population based study of antioxidants concluded that a diet rich in foods containing vitamin E might help protect some people against Alzheimer’s disease (AD). Vitamin E in the form of supplements was not associated with a reduction in the risk of AD.