Researchers Axelson in 1981 and Weiner in 1984 are originally credited with analyzing the metabolites in the urine of people exposed to excess intake of alcohol. Now this has been extrapolated to study the effect of medications used to treat persons who are habitually prone to overuse alcohol.
The metabolic problem areas connected to alcohol abuse or excess intake of alcohol are:
• Deficiencies in fat metabolism
• Thiamine deficiency
In other words, metabolic discrepancies in lipid metabolism and thiamine deficiency occur in people with a history of alcohol abuse and metabolomics can evaluate these discrepancies in terms of cause and effect. Understanding the factors responsible for alcohol-induced dys-functioning of these metabolic pathways could also help in the development of new medications to treat conditions that arise out of alcohol abuse.
Deficiencies in fat metabolism
Human body has to maintain a balance between the breakdown of lipids to produce energy and normal lipid synthesis. Excess alcohol intake impedes with this mechanism resulting in excess triglycerides in the liver and the blood causing a proportionate increase in the risks of contracting atherosclerosis and cardiac related illnesses. Excess alcohol intake can give rise to the condition dyslipidemia.
The fatty acid synthesis involving the synthesis of palmitates, stearates, and oleates in the liver were found diminished with excess intake of alcohol. On the contrary, oleate synthesis in the pancreas actually increased with excess alcohol intake while palmitate and stearate synthesis decreased. Only metabolomic studies can confirm this. Overall excess alcohol intake tends to increase fatty acids in liver cells as also decrease the synthesis of fatty acids. Oleate which is an unsaturated fatty acid, deals with removing saturated fatty acids from the liver. So less of oleate means it could lead to accumulation of fatty acids in the liver. Similarly if oleate is more in the pancreas it could result in pancreatitis and only metabolomic investigation can confirm this.
The factors that control gene activation in lipid metabolism also control lipid synthesis and its breakdown. A couple of these factors are:
• PPARs or peroxisomal proliferator --activated receptors: These are hormone receptors in cell nucleus whose activation enables conversion of lipids to energy. Ethanol inhibits its transcription activating properties. If PPARs don't function it leads to lipid metabolism deficiencies and insulin resistance.
• SREBPs or sterol response element-binding proteins 1 and -2: They work as sensors for fatty acid and cholesterol levels in blood/tissue and they help maintain constant levels of lipids in the body. Their activation inhibits conversion of lipids to energy. Ethanol activates it.
If PPARs don't function and if SREBPs are activated the result is a fatty liver due to lipid accumulation. This is what happens in alcohol related liver damage.
Altered lipid metabolism due to excess alcohol could lead to formation of reactive oxygen species which are small oxygen molecules that could damage tissues and allow the disease to spread rapidly.
Drugs that activate PPARs can counter the effects of alcohol overuse. The antihyperglycemic drug pioglitazone which can stimulate PPAR's has been experimentally used to treat fatty liver condition.
Currently in relation to lipid metabolites conventional measurement techniques evaluate for cholesterol esters or triglycerides. But metabolomics help detect more lipid metabolites and therefore we will be better able to assess how lipid metabolism relates to administration of a drug or disease condition. The LIPIDMAPS is a step in this direction.
LIPIDMAPS is an excellent endevour to:
• Distinguish, detect and characterize lipids in a specific cell.
• Quantify the lipid metabolites and the extent of metabolite level changes during cellular activity.
• Chart out lipid maps with the biochemical pathways that the lipids follow.
Thiamine is a vitamin required for the effective functioning of the cardiovascular, digestive and nervous systems. Apart from thiamine deficiency due to faulty nutritional intake, abnormal alcohol intake could also lead to lesser utilization of thiamine by the cells-----all of these are reasons for causing neuro-degeneration. People with habitually too much alcohol intake could be susceptible to brain degeneration-----not due to alcohol toxicity but due to thiamine deficiency. That apart, thiamine is a co-factor for some enzymes connected to carbohydrate metabolism.
The enzyme transketolase has a functional role to play in reactions that entail the pentose phosphate pathway. Similarly the enzymes PDH (pyruvate dehydrogenase) and KGDH ([alpha]-ketoglutarate dehydrogenase) have a pivotal role in reactions that involve the glycolysis and citric acid cycle. The one thing common to all these enzymes is that they require thiamine as a co-factor. So metabolomic studies that decipher the carbohydrate metabolism could help us understand how certain drug or alcohol induced states could lead to thiamine deficiency. That apart it could predict the possibility of neuro-degeneration.
Enzymes linked to metabolic disorders
DELTA]9-desaturase is an enzyme that is linked to metabolic disorders. In people with alcohol related problems, this enzyme shows increased activity. By finding out the fatty acids that are substrates for specific metabolic pathways one can learn about the enzymes that participate in the lipid synthesis and this in turn can help us to reckon with disease progression and also what happens when a remedial medicine/drug is administered.
Biomarkers for confirming alcohol overuse
Ethyl glucuronide (EtG) is a biomarker that remains in blood serum/plasma for several days subsequent to taking alcohol. Using metabolomic methods that involve proton NMR it is possible to detect EtG and hence vouch for alcohol consumption and the metabolic changes that occur subsequently.
Changes in metabolism of a particular class of metabolites could adversely affect changes in other metabolites as well. So understanding this interdependent activity could help us understand how disease progresses in different patient settings. Researchers have established that cardiovascular malfunction could be related to faulty lipid metabolism and also relate to a decline in mental powers. So at a practical level, excess intake of alcohol could not only affect metabolism in the brain but also bad effects on the liver. So if we can understand how different pathways integrate and co-regulate it could become the key to developing new medicines
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