الفهرس 
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Abstract
Lipids are a broad group of naturally occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The main biological functions of lipids include energy storage, as structural components of cell membranes, and as important signaling molecules. Biological lipids originate entirely or in part from two distinct types of biochemical subunits or ”building blocks”: ketoacyl and isoprene groups. Lipids may be divided into eight categories: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits). Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids), as well as other sterol containing metabolites such as cholesterol. The most abundant lipid constituents are triacylglycerols, free cholesterol, cholesterol esters and phospholipids (phosphatidylcholine and sphingomyelin especially) though fat soluble vitamins and anti-oxidants are also transported in this way. The ”fat-soluble” vitamins (A, D, E and K) which are isoprene based lipids are essential nutrients stored in the liver and fatty tissues, with a diverse range of functions.
Lipoproteins are complex aggregates of lipids and proteins that render the lipids compatible with the aqueous environment of body fluids and enable their transport throughout the body. A lipoprotein is a biochemical assembly that contains both proteins and lipids whose function is to transport water insoluble lipids in the water based bloodstream. The lipids or their derivatives may be covalently or non covalently bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins and toxins are lipoproteins. Examples include the high density (HDL) and low density (LDL) lipoproteins which enable fats to be carried in the blood stream, the transmembrane proteins of the mitochondrion and the chloroplast, and bacterial lipoproteins.
The main groups are classified as chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL) based on the relative densities of the aggregates on ultracentrifugation. The other important components of the lipoproteins are the apoproteins. The various types of apolipoproteins, are Apo A, ApoB, ApoC, ApoD , Apo E.
Apo E in three isoforms is synthesised by many tissues including liver, brain, adipose tissue, and artery wall, but most is present in plasma lipoproteins derived primarily from the liver. It is involved in many aspects of lipid and lipoprotein homeostasis, both for the triacylglycerol-rich lipoproteins and HDL, but it is also important for lipid metabolism in brain and other tissues. Apo E is especially important for cholesterol metabolism in the brain but excess of one specific form (apo E4) is associated with Alzheimer’s disease. It is seen as a target for therapeutic intervention in diseases of the central nervous system.
The apoproteins and lipoproteins contain a number of important enzymes including lipases acyl transferases transport proteins and some with anti oxidative or antinflammatory functions. The lipoproteins can be categorised simplistically according to their two main metabolic functions. The principal role of the chylomicrons and VLDL is to transport triacylglycerols as a source of fatty acids from the intestines or liver to the peripheral tissues. In contrast, the HDL remove excess cholesterol from peripheral tissues and deliver it to the liver for excretion in bile in the form of bile acids a process that has been termed reverse cholesterol transport.
The defects in lipoprotein metabolism such as hyper-or hypolipoproteinemias, abnormal lipoprotein metabolism is often observed as a secondary effect of diabetes, hypothyroidism and kidney disease. In Tangier disease patients have mutations in both copies of the genes that code for the ABCA 1 transporter protein so they have very little circulating HDL. The role of lipoproteins in the metabolism of triacylglycerol and cholesterol in relation to cardiovascular disease is highly complex and contentious. It is believed that HDL may protect against atherosclerosis via the promotion of reverse cholesterol transport. Higher concentrations of LDL cholesterol have been associated with increasing severity of cardiovascular disease although the experimental correlations are not as good as for HDL. This is the ‘bad cholesterol’. The apolipoproteins and associated enzymes of HDL are believed to be important for the maintenance of health in many further ways including antioxidant and anti thrombotic effects.
Dyslipidemia is a pathological increase of lipid and lipoprotein levels in the blood. Most prominent among these are the hyperlipidemic diseases hypercholesterolemia and hypertriglyceridemia. Most disturbances of lipid homeostasis are associated with a more sedentary lifestyle, excessive caloric intake, and age, and do frequently appear combined with each other.
Lipid metabolism is of particular interest due to its high concentration in CNS. The importance of lipids in cell signaling and tissue physiology is demonstrated by many CNS disorders and injuries that involve deregulated metabolism such as (Alzheimer’s, Parkinson’s; Niemann-Pick; Multiple sclerosis, Huntington, amyotrophic lateral sclerosis and epilepsy) and CNS injury (Stroke, traumatic brain injury; and spinal cord injury).
A stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain caused by a blocked or burst blood vessel. This can be due to ischemia or due to a hemorrhage. Because stroke may indicate underlying atherosclerosis. It is important to determine the patients risk for other cardiovascular diseases such as coronary heart diseases.
The most important modifiable risk factors for stroke are high blood pressure and arterial fibirilation. Other modifiable risk factors include high blood cholesterol levels and diabetes and cigarette smoking and lack of physical activity and obesity and unhealthy diet and alcohol use could predispose to ischemic stroke and intracerebral and subarachnoid hemorrhage. The drugs most commonly associated with stroke are cocaine and amphetamines causing hemorrhagic strok. Best medical management for stroke includes advice on diet, exercise, smoking and alcohol use and drug therapy is the most common method of stroke prevention.Statins have been shown to reduce the risk of stroke by about 15%. The success of statin drugs in clinical trials is based on some reductions in mortality rates.
Alzheimer’s disease (AD) it also called Senile Dementia of the Alzheimer. Alzheimer’s is the most common form of dementia. Generally it is diagnosed in people over 65 years of age although the less-prevalent early onset Alzheimer’s can occur much earlier is a progressive brain disorder affecting regions that control memory and cognitive functions. One of the halmarks of AD is ovrproduction of a 4-kDa peptide,amyloid B-peptide, resulting in formation of plaques. The amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease. A po E was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. It has been studied for its role in several biological processes not directly related to lipoprotein transport including Alzheimer’s disease (AD) immunoregulation and cognition. Alzheimer’s Disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break down of this peptide, both within and between cells. Oxidative stress is a significant cause in the formation of the pathology.
Altough cardiovascular risk factors such as hypercholesterolemia, hypertension and diabetes are associated with a higher risk of onest and course of AD.
Parkinson’s disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impair a motor skills, speech, and other functions. Parkinson’s disease belongs to s a group of conditions called movement disorders. It is characterized by muscle rigidity and tremor and slowing of physical movement (bradykinesia) and a loss of physical movement (akinesia) in extreme cases. PD is both chronic and progressive. PD is the most common cause of chronic progressive parkinsonism a term which refers to the syndrome of tremor, rigidity, bradykinesia and postural instability. PD is also called ”primary parkinsonism” or ”idiopathic PD”. It is chracterized by selective degeneration of dopaminergic neurons of the substantia nigra. The etiology of PD is unknown. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha synuclein. In Parkinson diseases The mechanism by which the brain cells in Parkinson’s are lost may consist of an abnormal accumulation of the protein alpha synuclein bound to ubiquitin in the damaged cells. The alpha synuclein- ubiquitin complex cannot be directed to the proteasome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies.
Niemann Pick disease refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases (LSD). Niemann Pick diseases are genetic diseases which are classified in a subgroup of LSDs called sphingolipidoses or lipid storage disorders in which harmful quantities of fatty substances, or lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain. Mutations in the SMPD1 gene cause Niemann Pick disease types A and B, and mutations in NPC1 and NPC2 cause Niemann-Pick disease, type C (NPC). Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann Pick.
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin. In MS, the body’s own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. The name multiple sclerosis refers to scars (scleroses-better known as plaques or lesions) particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin. Theories include genetics or infections. Different environmental risk factors have also been found. MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the individual’s genetics and as yet unidentified environmental insults. The immune system may play a role in demyelination associated with such diseases including inflammation causing demyelination by overproduction of cytokines via upregulation of tumor necrosis factor (TNF) or interferon. The other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS the inflammatory process is caused by T cells a kind of lymphocyte. MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem, basal ganglia and spinal cord and the optic nerve. The function of white matter cells is to carry signals between grey matter areas where the processing is done and the rest of the body. The peripheral nervous system is rarely involved. MS destroys oligodendrocytes the cells responsible for creating and maintaining a fatty layer known as the myelin sheath which helps the neurons carry electrical signals. Demyelination is the loss of the myelin sheath insulating the nerves and is the hallmark of some neurodegenerative autoimmune diseases including multiple sclerosis acute disseminated encephalomyelitis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome, central pontine myelinosis, inherited demyelinating diseases such as Leukodystrophy, and Charcot Marie Tooth.
Amyotrophic lateral sclerosis is a form of motor neuron disease. ALS is a progressive fatal neurodegenerative disease caused by the degeneration of motor neurons the nerve cells in the central nervous system that control voluntary muscle. The disorder causes muscle weakness and atrophy throughout the body as both the upper and lower motor neurons degenerate ceasing to send messages to muscles. Unable to function the muscles gradually weaken develop fasciculations because of denervation and eventually atrophy because of that denervation. ALS is associated with frontotemporal dementia. There are reports of more subtle cognitive changes of the frontotemporal type in many patients when detailed neuropsychological testing is employed. Sensory nerves and the autonomic nervous system which controls functions like sweating generally remain functional. The familial ALS has been linked to a mutation on the gene coding for superoxide dismutase (a critical enzyme involved in the protection of mitochondria against oxidative stress). The progressive damage to the mitochondria is at the central mechanism in age related change implying that damage to the mitochondria may be a common denominator in all age related neurodegenerative diseases. There is a known hereditary factor in familial ALS (FALS) there is no known hereditary component in the 90-95% cases diagnosed as sporadic ALS. An inherited genetic defect on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS. Dietary intake of polyunsaturated fatty acids (PUFA) has been shown in several studies to decrease the risk of developing ALS and other neurodegenerative diso shown in several studies to decrease the risk of developing ALS and other neurodegenerative disorders probably through several mechanisms including promotion of neurotrophins.
Hypolipidemic agents or antihyperlipidemic agents, are a diverse group of lipid lowering drugs (LLD) that are used in the treatment of hyperlipidemias. There are several classes of hypolipidemic drugs. They may differ in both their impact on the cholesterol profile and adverse effects. For example some may lower the ”bad cholesterol” low density lipoprotein (LDL) more so than others while others may preferentially increase high density lipoprotein (HDL) ”the good cholesterol”. Clinically the choice of an agent will depend on the patient’s cholesterol profile, cardiovascular risk and the liver and kidney functions of the patient evaluated against the balancing of risks and benefits of the medications.
Statins lower cholesterol by inhibiting the enzyme HMG CoA reductase which is the rate limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors resulting in an increased clearance of low density lipoprotein (LDL) from the bloodstream. The first results can be seen after one week of use and the effect is maximal after four to six weeks. Scandinavian Simvastatin Survival Study supported the use of statins in secondary prevention for cardiovascular disease or as primary prevention only when the risk for cardiovascular disease was significantly. Heart Protection Study (HPS) showed preventative effects of statin use in specific risk groups such as diabetics.
Commenly prescribed statins include:
• Atorvastatin (L ipitor).
• Fluvastatin (Lescol, Lescol XL).
• Lovastatin (Mevacor, Altocor).
• Pravastatin (Pravachol).
• Rosuvastatin (Crestor).
• Simvastatin (Zocor).
Fibrates in pharmacology the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders mainly hypercholesterolemia and are therefore hypolipidemic agents. Hypolipidemic agents or antihyperlipidemic agents, Fibrates are used in accessory therapy in many forms of hypercholesterolemia usually in combination with statins. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non fatal heart attack but do not improve all cause mortality and are therefore only indicated in those not tolerant to statins. Although less effective in lowering LDL fibrates improve HDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels and seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2). They are used in many hyperlipidemias.