اليابان تطلق لاب توب يشحن بالماء

اليابان تطلق لاب توب يشحن بالماء

وكالات طوكيو / فكر مصممو ذلك الكمبيوتر في توفير الطاقة وكذلك استخدام الطاقة النظيفة لشحن الأجهزة في المستقبل، كتوفير للكهرباء فمع زيادة استخدام الأجهزة قد يعاني العالم من نقص في الكهرباء ! فما هو الحل ! الحل هو استخدام كوب واحد من المياه لشحن البطارية !! قد تندهش من الفكرة بالطبع ولكن ربما تقتنع بها وهو ما سوف يعمل عليه لإنتاج أول صيحة منه ليصبح حقيقة قريباً .

شرح مصممو ذلك الجهاز وهما اليابانيان هايرم كيم وسين جي بيك كيفية عمله إن النظام يستخدم خزان المياه الخارجية وهو يعتبر بطارية ذلك الجهاز، والجميع يعلم أن المياه عنصراها هما الهيدروجين والأكسجين ، وهما بالتحديد مولد الطاقة لذلك الجهاز، فما إن يتم وضع البطارية التي هي خزان الجهاز في كوب المياه يقوم ذلك الخزان بامتصاص المياه، وبعد وضعه وتركيبه في الجهاز يقوم بتوليد الطاقة من خلال صمام خاص بالجهاز عن طريق الأكسجين والهيدروجين و تفاعلهما داخل ذلك الصمام.

وفي الصور توضح لكم البطارية أو خزان المياه الذي يخزن المياه بداخله ويمكنك من خلال الشريط الأخضر المضئ فوقه التعرف ما إذا كان الخزان قد امتلئ أم لا .

قد يكون ذلك الجهاز مدهش لكم فقط لإنه يمكنه توليد طاقته من المياه فقط ، ولكن هذه ليست فقط مزاياه فنحن في البداية فقط، ما يميز ذلك الجهاز أيضاً هو سهولة حملة من مكان لآخر وذلك لانه يتم طيه بسهولة.

قد تسأل لماذا ذلك الجاهز في تم تصميمه باللون الأخضر فقط !! بالطبع بعد سرد الموضوع والشرح يمكنك بسهوله الإجابة على ذلك السؤال فكما تعتمد الطبيعة والبيئة علي المياه بعنصريه وأيضاً الأكسجين الذي هو أحد عناصر المياه، فتري ذلك الجهاز يعتمد أيضا عليهما ولذلك تم ربطه بالطبيعة والأهم إنه يساعد في الحفاظ على البيئة وأستخدام الطاقة النظيفة فقط.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

An Introduction to ELISA

• Overview
• Basic ELISA Procedure
• Antibodies and Antigens in ELISA
• Four typical ELISA formats
• ELISA Detection Options
• ELISA Results
• Sensitivity

Overview

The enzyme-linked immunosorbent assay (ELISA) is a common laboratory technique which is used to measure the concentration of an analyte (usually antibodies or antigens) in solution. The basic ELISA, or enzyme immunoassay (EIA), is distinguished from other antibody-based assays because separation of specific and non-specific interactions occurs via serial binding to a solid surface, usually a polystyrene multiwell plate, and because quantitative results can be achieved. The steps of the ELISA result in a colored end product which correlates to the amount of analyte present in the original sample.

ELISAs are quick and simple to carry out, and since they are designed to rapidly handle a large numbers of samples in parallel, they are a very popular choice for the evaluation of various research and diagnostic targets. Figure 1 shows a typical ELISA result.

ELISAs were first developed in the early 1970s as a replacement for radioimmunoassays. They remain in wide use in their original format and in expanded formats with modifications that allow for multiple analytes per well, highly sensitive readouts, and direct cell-based output.

Basic ELISA Procedure

ELISAs begin with a coating step, where the first layer - either an antigen or an antibody - is adsorbed to a polystyrene 96 well plate. (Adsorption is the passive attachment of a liquid to a solid surface creating a thin film.) Coating is followed by blocking and detection steps as shown in the simple schematic diagram below.

Since the assay uses surface binding for separation, several washes are repeated between each ELISA step to remove unbound materials. During this process it is essential that excess liquid is removed in order to prevent the dilution of the solutions added in the next stage. For greatest consistency specialized plate washers are used.

ELISAs can be quite complex, including various intervening steps and the ability to measure protein concentrations in heterogeneous samples such as blood. The most complex and varying step in the overall process is detection, where multiple layers of antibodies can be used to amplify signal.

Figure 2. ELISA overview flowchart and schematic.

Antibodies and Antigens in ELISA

All ELISAs rely on the specific interaction between an epitope, a small linear or three dimensional sequence of amino acids found on an antigen, and a matching antibody binding site. The antibodies used in an ELISA can be either monoclonal (derived from unique antibody producing cells called hybridomas and capable of specific binding to a single unique epitope) or polyclonal (a pool of antibodies purified from animal sera that are capable of binding to multiple epitopes).

There are four basic ELISA formats, allowing for a certain amount of flexibility which can be adjusted based on the antibodies available, the results required, or the complexity of the samples.

It is possible to use both monoclonals and polyclonals in an ELISA; however, polyclonals are more typically used for the secondary detection layer in indirect ELISAs, while monoclonal antibodies are more typically used for capture or primary detection of the antigen.

Four Typical ELISA Formats

The ELISA provides a wealth of information in its simplest formats, but it can also be used in more complex versions to provide enhanced signal, more precise results, or if certain reagents are not available. The four typical ELISA formats are described briefly below. The end result for all the ELISAs is shown in figure 3, a single well, or a series of wells in a multiwall dish, with color intensity varying in proportion to the amount of antigen/analyte in the original sample.

Direct ELISA
An antigen coated to a multiwell plate is detected by an antibody that has been directly conjugated to an enzyme. This can also be reversed, with an antibody coated to the plate and a labeled antigen used for detection, but the second option is less common.

This type of ELISA has two main advantages:

• It is faster, since fewer steps are required
• It is less prone to error, since there are fewer steps and reagents

Indirect ELISA
Antigen coated to a polystyrene multiwell plate is detected in two stages or layers. First an unlabeled primary antibody, which is specific for the antigen, is applied. Next, an enzyme-labeled secondary antibody is bound to the first antibody. The secondary antibody is usually an anti-species antibody and is often polyclonal.

This method has several advantages:

• Increased sensitivity, since more than one labeled antibody is bound per primary antibody
• Flexibility, since different primary detection antibodies can be used with a single labeled secondary antibody
• Cost savings, since fewer labeled antibodies are required

Sandwich ELISA
Sandwich ELISAs typically require the use of matched antibody pairs, where each antibody is specific for a different, non-overlapping part (epitope) of the antigen molecule. The first antibody, termed the capture antibody, is coated to the polystyrene plate. Next, the analyte or sample solution is added to the well. A second antibody layer, the detection antibody, follows this step in order to measure the concentration of the analyte. Polyclonals can also be used for capture and/or detection in a sandwich ELISA provided that variability is present in the polyclonal to alow for both capture and detection of the analyte through different epitopes.

If the detection antibody is conjugated to an enzyme, then the assay is called a direct sandwich ELISA. If the detection antibody is unlabeled, then a second detection antibody will be needed resulting in an indirectsandwich ELISA.

This type of assay has several advantages:

• High specificity, since two antibodies are used the antigen/analyte is specifically captured and detected
• Suitable for complex samples, since the antigen does not require purification prior to measurement
• Flexibility and sensitivity, since both direct and indirect detection methods can be used

Competition or Inhibition ELISA
This is the most complex ELISA, and is used to measure the concentration of an antigen (or antibody) in a sample by observing interference in an expected signal output. Hence, it is also referred to as an inhibition ELISA. It can be based upon any of the above ELISA formats, direct, indirect, or sandwich, and as a result it offers maximum flexibility in set up.

It is most often used when only one antibody is available to the antigen of interest or when the analyte is small, i.e. a hapten, and cannot be bound by two different antibodies.

A simple example of a competitive ELISA is shown in figure 7. In this case samples are added to an ELISA plate containing a known bound antigen. After coating, blocking, and washing steps, unknown samples are added the plate. Detection then follows pretty much as with other ELISA formats. If the antigen in the sample is identical to the plate-adsorbed antigen, then there will be competition for the detection antibody between the bound and free antigen. If there is a high concentration of antigen in the sample, then there will be a significant reduction in signal output of the assay. Conversely, if there is little antigen in the sample, there will be minimal reduction in signal.

Therefore, with a competition ELISA, one is actually measuring antigen concentration by noting the extent of the signal reduction. If the detection antibody is labeled, then this would be a direct competition ELISA and if unlabeled, then this would be an indirect competition ELISA.

For further examples of competition ELISAs, and a thorough explanation of this technique, please refer to The ELISA Guidebook (Crowther 2001).

Figure 7. Competition ELISA. Bound and free antigen compete for binding to a labeled detection antibody.

ELISA Detection Options

ELISAs, by definition, take advantage of an enzymatic label to produce a detectible signal that is directly correlated to the binding of antibody to an antigen. There are a few different types of enzymes and enzyme substrates that are typically used for ELISAs and a few slightly different methods for incorporating the enzyme step into the process. The final assay signal is measured with a spectrophotometric or fluorescent plate reader (depending upon the substrate chosen).

One aspect of ELISA terminology that often leads to confusion is the variability in the way the terms direct and indirect are applied. We will adhere to the use of these terms as they apply to the detection portion of the assay as indicated below:

Direct detection
Antibodies are directly labeled with alkaline phosphatase (AP) or horseradish peroxidase (HRP); this is the most common ELISA detection strategy. HRP and AP substrates typically produce a colorimetric output that is read by a spectophotometer. Detection can also occur by fluorescently-labeled antibodies [here the assay is usually termed a fluorescence-linked immunosorbent assay (FLISA)]

Indirect detection
Antibodies are coupled to biotin, followed by a streptavidin-conjugated enzyme step; this is most common.

Additionally, it is possible to use unlabeled primary antibodies followed by enzyme-coupled or biotinylated secondary antibodies. If the secondary antibody is biotinylated, then a tertiary step is required for detection. In this case treatment with the streptavidin-enzyme conjugate, followed by an appropriate substrate.

ELISA Results

The ELISA assay yields three different types of data output:

1) Quantitative:
ELISA data can be interpreted in comparison to a standard curve (a serial dilution of a known, purified antigen) in order to precisely calculate the concentrations of antigen in various samples.

2) Qualitative:
ELISAs can also be used to achieve a yes or no answer indicating whether a particular antigen is present in a sample, as compared to a blank well containing no antigen or an unrelated control antigen.

3) Semi-quantitative:
ELISAs can be used to compare the relative levels of antigen in assay samples, since the intensity of signal will vary directly with antigen concentration.

ELISA data is typically graphed with optical density vs log concentration to produce a sigmoidal curve as shown in Figure 8. Known concentrations of antigen are used to produce a standard curve and then this data is used to measure the concentration of unknown samples by comparison to the linear portion of the standard curve. This can be done directly on the graph or with curve fitting software which is typically found on ELISA plate readers.

Figure 8. A typical ELISA standard curve.

Sensitivity

ELISAs are one of the most sensitive immunoassays available. The typical detection range for an ELISA is 0.1 to 1 fmole or 0.01 ng to 0.1 ng, with sensitivity dependent upon the particular characteristics of the antibody –antigen interaction. In addition, some substrates such as those yielding enhanced chemiluminescent or fluorescent signal, can be used to improve results. As mentioned earlier, indirect detection will produce higher levels of signal and should therefore be more sensitive. However, it can also cause higher background signal thus reducing net specific signal levels.

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Events

MEDICADüsseldorf, GermanyNovember 14-17, 2012

2nd Munich Biomarker ConfMunich, GermanyNovember 22-23, 2012

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------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Reverse Cholesterol Transport and the Role of HDLc

Q.- What is Reverse cholesterol transport ? Explain the biological/clinical significance of this process.

Or

Discuss the concept of “reverse cholesterol transport” and indicate how its operation might contribute to a lowering of serum cholesterol.

or

Discuss the role of LCAT (Lecithin Cholesterol Acyl Transferase) in the cholesterol transport.

Answer-  The selective transfer of cholesterol from peripheral cells to HDLs, and from HDLs to the liver for bile acid synthesis, and to steroidogenic tissues for hormone synthesis, is a key component of cholesterol homeostasis. This is in part the basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis, and because of this only HDL is designated as "Good cholesterol carrier".

HDL- HDL particles serve as  circulating reservoir of apo CII (apo protein that is transferred to VLDL and Chylomicrons, and is an activator of lipoprotein lipase), and apo E (the apoprotein required for the receptor-mediated endocytosis of IDls and chylomicron remnants (Figure-1)

Figure-1 Showing the structure of HDL. The outer shell is made by apoproteins, phospholipids and free cholesterol and the inner core is made by Cholesteryl esters and triglycerides.

HDL is synthesized and secreted from both liver and intestine (Figure -2). However, apo C and apo E are synthesized in the liver and transferred from liver HDL to intestinal HDL when the latter enters the plasma. Nascent HDL consists of discoid phospholipid  bilayer containing apo A and free cholesterol.

Figure-2- Showing the role of HDL in reverse cholesterol transport. HDL has four forms, Discoidal HDL, HDL3 , HDL2 and Pre β  HDL.( C- Cholesterol, CE- Cholesteryl Ester, LCAT- Lecithin choleterol Acyl Transferase, PL- Phospholipid.

Reverse cholesterol transport involves-

1) Efflux of cholesterol from peripheral cells and esterification to form cholesteryl ester by LCAT

LCAT ( Lecithin Cholesterol Acyl Transferase) enzyme catalyzes the esterification of cholesterol to form Cholesteryl ester.

The reaction can be represented as follows-

Lecithin + Cholesterol ---------->   Lysolecithin + Cholesteryl Ester

LCAT and the LCAT activator apo A-I—bind to the discoidal particles (Figure-1) and the surface phospholipid , free cholesterol  (extracted from peripheral cells) is converted into cholesteryl esters and lysolecithin .

The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer, whereas lysolecithin is transferred to plasma albumin. Thus, a nonpolar core is generated, forming a spherical, pseudomicellar HDL covered by a surface film of polar lipids and apolipoproteins. This aids the removal of excess unesterified cholesterol from lipoproteins and tissues .

2) Binding of the cholesteyl ester-rich HDL(HDL2) to liver and steroidogenic cells, and the selective transfer of cholesteryl esters in to these cells)- Figure-2

HDL Receptor

The class B scavenger receptor B1 (SR-B1) has been identified as an HDL receptor with a dual role in HDL metabolism.

a) In the liver and in steroidogenic tissues, it binds HDL via apo A-I, and cholesteryl ester is selectively delivered to the cells, although the particle itself, including apo A-I, is not taken up.

b) In the tissues, on the other hand, SR-B1 mediates the acceptance of cholesterol from the cells by HDL, which then transports it to the liver for excretion via the bile (either as cholesterol or after conversion to bile acids) in the process known as reverse cholesterol transport (Figure 2).

HDL cycle

HDL₃, generated from discoidal HDL by the action of LCAT (Figure-2) accepts cholesterol from the tissues via the SR-B1 and the cholesterol is then esterified by LCAT, increasing the size of the particles to form the less dense HDL₂.

HDL₃ is then reformed, either after selective delivery of cholesteryl ester to the liver via the SR-B1 or by hydrolysis of HDL₂ Phospholipid and triacylglycerol by hepatic lipase (Figure-2).This interchange of HDL₂ and HDL₃ is called the HDL cycle (Figure -2).

Free apo A-I is released by these processes and forms pre-HDL after associating with a minimum amount of Phospholipid and cholesterol. Surplus apo A-I is destroyed in the kidney.

HDL Transporter

A second important mechanism for reverse cholesterol transport involves the ATP-binding cassette transporter A1 (ABCA1) (Figure-2). ABCA1 is a member of a family of transporter proteins that couple the hydrolysis of ATP to the binding of a substrate, enabling it to be transported across the membrane. ABCA1 preferentially transfer cholesterol from cells to poorly lipidated particles such as pre-HDL or apo A-1, which are then converted to HDL₃ via discoidal HDL (Figure -2). Pre-β HDL is the most potent form of HDL inducing cholesterol efflux from the tissues.

Clinical Significance

LCAT deficiency- Complete absence (Familial LCAT deficiency) or partial (Fish eye disease) deficiency results in a marked decrease in HDL primarily as a result of the hyper catabolism of lipid poor HDLs.

Atherosclerosis- There is an inverse relationship between HDL (HDL₂) concentrations and coronary heart disease. This is consistent with the function of HDL in reverse cholesterol transport. Atherosclerosis is characterized by the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins into the artery wall. Diseases in which prolonged elevated levels of VLDL, IDL, chylomicron remnants, or LDL occur in the blood (eg, diabetes mellitus, lipid nephrosis, hypothyroidism, and other conditions of hyperlipidemia) are often accompanied by premature or more severe atherosclerosis.LDL:HDL cholesterol ratio a good predictive parameter.

Low HDL levels

Causes of low HDL levels

• Severely reduced plasma levels of HDL-C (<20 mg/dL) accompanied by triglycerides <400 mg/dL usually indicate the presence of a genetic disorder, such as a mutation in apoA-I, LCAT deficiency, or Tangier disease.
• HDL-C levels <20 mg/dL are common in the setting of severe hypertriglyceridemia,
• HDL-C levels <20 mg/dL also occur in individuals using anabolic steroids.
• Secondary causes of more moderate reductions in plasma HDL (20–40 mg/dL) should be considered like smoking, diabetes mellitus Type 2, Gaucher’s disease and malnutrition.

Management of low HDL levels

•  Smoking should be discontinued,
• Obese persons should be encouraged to lose weight,
• Sedentary persons should be encouraged to exercise, and diabetes should be optimally controlled.
•  When possible, medications associated with reduced plasma levels of HDL-C should be discontinued.
• The presence of an isolated low plasma level of HDL-C in a patient with a borderline plasma level of LDL-C should prompt consideration of LDL lowering drug therapy in high-risk individuals.
• Statins increase plasma levels of HDL-C only modestly (~5–10%). Fibrates also have only a modest effect on plasma HDL-C levels (increasing levels ~5–15%), except in patients with coexisting hypertriglyceridemia, where they can be more effective.
• Niacin is the most effective available HDL-C–raising therapeutic agent and can be associated with increases in plasma HDL-C by up to ~30%, although some patients do not respond to niacin therapy.

 ------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Ravi_Sirdeshmukh

https://www.researchgate.net/profile/Ravi_Sirdeshmukh/

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Biochemistry of Fatty Liver

By Dr. Namrata Chhabra

Q.- Give a brief account of the steps of synthesis of Very Low density lipoprotein (VLDL). High light the clinical significance of impaired VLDL synthesis.

Answer- There are striking similarities in the mechanisms of formation of chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells (Figure -1), perhaps because—apart from the mammary gland—the intestine and liver are the only tissues from which particulate lipid is secreted.

Steps of synthesis-

1) Protein synthesis- The major apoprotein of VLDL, Apo B100 is synthesized in the rough endoplasmic reticulum. VLDL particles are stabilized by two lipoproteins apo B-100 and apo E (34 kd). Apo B-100, one of the largest proteins known (513 kd), is a longer version of apo B-48. Both apo B proteins are encoded by the same gene and produced from the same initial RNA transcript. In the intestine, RNA editing modifies the transcript to generate the mRNA for apo B-48, the truncated form.

Newly secreted VLDL contains only a small amount of apolipoproteins C and E, and the full complement is acquired from HDL in the circulation.

2) Lipid synthesis and formation of lipoprotein –In the fully fed state, apo B-100 is synthesized in excess of requirements for VLDL secretion and the surplus is destroyed in the liver (Figure-2). During translation of apo B-100, microsomal transfer protein-mediated lipid transport enables lipid to become associated with the nascent polypeptide chain.

The liver is a major site of triacylglycerol and cholesterol synthesis. Triacylglycerols and cholesterol in excess of the liver’s own needs are exported into the blood in the form of very low density lipoproteins (d<1.006 g cm-3).

After release from the ribosomes, these particles fuse with more lipids from the smooth endoplasmic reticulum, producing nascent VLDL.

3) Glycosylation and release of VLDL- After addition of carbohydrate residues in golgi apparatus, VLDL particles are released from the cell by reverse pinocytosis. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

Figure-1- Showing the steps of synthesis of VLDL in the liver cell, (RER- Rough endoplasmic reticulum, SER- Smooth endoplasmic reticulum, G- Golgi apparatus, N- Nucleus, S- Space of Disse and VLDL- very low density lipoprotein)

Clinical Significance

Fatty liver (steatosis)

 It is an abnormal accumulation of certain fats (triglycerides) inside liver cells.

Hepatic triacylglycerol synthesis provides the immediate stimulus for the formation and secretion of VLDL. Impaired VLDL formation or secretion leads to nonmobilization of lipid components from the liver, resulting in fatty liver.

Causes of fatty liver- Imbalance in the rate of triacylglycerol formation and export causes fatty liver. For a variety of reasons, lipid—mainly as triacylglycerol—can accumulate in the liver. Extensive accumulation is regarded as a pathologic condition. When accumulation of lipid in the liver becomes chronic, fibrotic changes occur in the cells that progress to cirrhosis and impaired liver function.

Fatty livers fall into two main categories-

A) More synthesis of Triglycerides or

B) Defective VLDL synthesis (Metabolic block)

A) More synthesis of Triglycerides-Triglycerides are synthesized in excess due to more availability of Fatty acid and glycerol. The fatty acids used are derived from two possible sources: (1) synthesis within the liver from acetyl-CoA derived mainly from carbohydrate (perhaps not so important in humans) and (2) uptake of free fatty acids from the circulation. The first source is predominant in the well-fed condition, when fatty acid synthesis is high and the level of circulating free fatty acids is low. As triacylglycerol does not normally accumulate in the liver under this condition, it must be inferred that it is transported from the liver in VLDL as rapidly as it is synthesized and that the synthesis of apo B-100 is not rate-limiting. Free fatty acids from the circulation are the main source during starvation, the feeding of high-fat diets, or in diabetes mellitus, when hepatic lipogenesis is inhibited.

Thus high carbohydrate diet stimulates de novo fatty acid synthesis by providing excess of Acetyl CoA and high fat feeding provides more flux of fatty acids from the diet that can be esterified to provide excess triglycerides.

B) Defective VLDL synthesis The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate.

Theoretically, the lesion may be due to-

 (1) A block in apolipoproteins synthesis-

Causes- can be-

a) Protein energy Malnutrition

b) Impaired absorption

c) Presence of inhibitors of endogenous  protein synthesis e.g.- Carbon tetra chloride, Puromycin, Ethionine etc. The antibiotic puromycin, ethionine (α-amino-γ-mercaptobutyric acid), carbon tetrachloride, chloroform, phosphorus, lead, and arsenic all cause fatty liver and a marked reduction in concentration of VLDL (Figure-2). The action of ethionine is thought to be caused by a reduction in availability of ATP due to its replacing methionine in S-adenosylmethionine, trapping available adenine and preventing synthesis of ATP.

d) Hypobetalipoproteinemia- Defective apo B gene can cause impaired synthesis of apo B protein.

(2) A failure in provision of phospholipids that are found in lipoproteins-

a) A deficiency of choline, which has therefore been called a lipotropic factor can cause impaired formation of phosphatidyl choline (Lecithin),a glycerophospholipid (Figure-2)

b) Choline is formed by methylation from ethanolamine, with S-Adenosyl Methionine acting as a methyl group donor. Methionine deficiency can cause impaired choline synthesis and thus fatty liver besides other clinical defects.

c) Deficiency of essential fatty acids- can also lead to impaired Phospholipid synthesis

(3) Impaired Glycosylation- Orotic acid causes fatty liver; it is believed to interfere with glycosylation of the lipoprotein, thus inhibiting release, and may also impair the recruitment of triacylglycerol to the particles. In conditions of orotic aciduria (disorder of  pyrimidine nucleotide biosynthesis), fatty liver can be observed (Figure-2)

4) Impaired secretion of VLDL- oxidative stress is a common cause for membrane disruption of lipoprotein. The action of carbon tetrachloride probably involves formation of free radicals causing lipid peroxidation (Figure-2). Some protection against this is provided by the antioxidant action of vitamin E-C, beta carotene and selenium in the supplemented diets.

Figure-2- Showing the biochemical basis of fatty liver disease. Imbalance in the rate of triacylglycerol formation and export causes fatty liver.

Clinical conditions causing fatty liver-Clinically fatty liver is of two types-

1) Non alcoholic fatty liver- Fatty liver (with or without fibrosis) due to any condition except alcoholism is called nonalcoholic steatohepatitis (Macro vesicular steatosis).

Causes of nonalcoholic steatosis or NAFLD are

• Obesity
• Diabetes mellitus
• Hypertriglyceridemia
• Drugs- corticosteroids, amiodarone, diltiazem, tamoxifen, highly active antiretroviral therapy
• Poisons (carbon tetrachloride and yellow phosphorus)
• Endocrinopathies such as Cushing’s syndrome and hypopituitarism, hypobetalipoproteinemia and other metabolic disorders,
• Obstructive sleep apnea,
• Starvation

(The biochemical basis for each condition has been explained above)

2) Alcoholic fatty liver- Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately cirrhosis. The fatty liver is caused by a combination of impaired fatty acid oxidation and increased lipogenesis, which is thought to be due to changes in the [NADH]/[NAD⁺] redox potential in the liver, and also to interference with the action of transcription factors regulating the expression of the enzymes involved in the pathways.

Oxidation of ethanol by alcohol and aldehyde dehydrogenase leads to excess production of NADH (Figure-3)

Figure-3- Showing steps of metabolism of alcohol

A) Effect of excess NADH – More triglyceride synthesis

1) The NADH generated competes with reducing equivalents from other substrates, including fatty acids, for the respiratory chain, inhibiting their oxidation and causing increased esterification of fatty acids to form triacylglycerol, resulting in the fatty liver.

2)  Oxidation of ethanol, leads to the formation of acetaldehyde, which is oxidized by aldehyde dehydrogenase, producing acetate. Acetate is converted to Acetyl coA and there is more fatty acid synthesis.

3) Accumulation of NADH causes more formation of Glycerol-3-P (shift of equilibrium of reaction), that can be used for the synthesis of triglycerides.

B) Improper apo- protein synthesis – Malnutrition is a common finding in chronic alcoholism There is less availability of essential amino acids.

C) Impaired Phospholipid synthesis-Due to malnutrition there is less availability of essential fatty acids and choline leading to defective Phospholipid synthesis.

D) Impaired secretion of VLDL- chronic alcohol consumption is associated with oxidative stress that can cause impaired VLDL secretion.

Thus multiple factors are responsible for alcoholic fatty liver disease

Lipotropic agents- Agents such as choline, Inositol, Methionine and other essential amino acids, essential fatty acids, anti oxidant vitamins, vitamin B12, folic acid and synthetic antioxidants which have the apparent effect of removal of fats from the liver cells, and thus prevent the formation of fatty liver are called lipotropic agents.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------