Metabolomics/Metabolites/Lipids/Energy Storage

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Lipidomics

L ctionality in cells extends to, but is not limited to, maintaining electrochemical gradients, subcellular partitioning, first- and second-messenger cell signaling, energy storage, protein trafficking and membrane anchoring. Physiological importance of lipids is evident when considering or observing lipid abnormalities, such as atherosclerosis, diabetes, obesity and Alzheimer's disease. Lipidomics "is a systems-based study of all lipids, the molecules with which they interact, and their function within a cell." The detection of various lipid species has been made more efficient with advances in soft-ionization mass spectrometry, combined with modern separation techniques. Lipid profiles are characterized as a mass spectrum of the composition and abundance of lipids contained from a crude lipid extract, and could be monitored over time and when responding to specific stimuli. Integrated with genomics, proteomics and metabolomics, lipidomics is expected to allow researchers to develop a better understanding of lipid functionality, in biological systems. In addition, researchers are expecting a better understanding on lipid-based disease mechanisms, for biomarker screening, and for monitoring pharmacologic therapy, as a result of lipidomic advances.

Systems biology signifies a vast impact on the future of disease treatment and prevention. The growing interest in the influence of lipids on systems biology owes largely to advances in mass spectrometry, which allow for detailed lipid profiles from minimal sample preparation. One of the developing groups involved in lipidome analysis, Lipid Metabolites and Pathways Strategy, is a consortium that has undertaken determining the complete lipidome of the mouse macrophage and its responses to a variety of stimuli, including oxidized lipids and lipopolysaccharides. Therapeutics are anticipated to advance with lipidomics as the effects of lipids on pathologic states, and influences that interfere with these effects become better understood. Integrating lipidomic data with genetic, proteomic, and metabolomic data proves to be a difficult endeavor, but will supposedly generate new modeling paradigms.

References:

http://www.jlr.org/cgi/content/full/47/10/2101

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Researching differential meal fat uptake into adipose tissue depots was conducted to determine the impact of this uptake on body fat distribution. The meal fat tracer/adipose tissue biopsy approach was employed, in order to compare the effects of meal fat content on the fat uptake into visceral, upper body, and lower body subcutaneous fat depots. Fat content was monitored in premenopausal women subjects. In addition, Fatty acids intake, from normal-fat and high-fat meals, was traced with [3H]triolein.

Experimental results indicate that the proportion of dietary fat uptake into the three monitored depots was not different, between meals. Visceral fat accumulation accounted for approximately five percent of meal fat disposal, without respect to visceral fat mass. Subjects consuming normal-fat meals had an increase in meal fatty acid uptake into femoral fat, as a function of leg fat mass. This increase is identified as an increased efficiency of uptake. There was, however, an opposite pattern observed in the effects of normal-fat meals on omental fat, and high-fat meals on all monitored fat depots. Approximately forty percent of meal fat was oxidized, for both types of meals, after twenty-four hours.

Researchers concluded that greater thigh adipose tissue in women is directly associated with greater efficiency of meal fat storage, under specific energy balance conditions. However, an opposite trend was observed in visceral fat. These inferences indicate the possibility of different mechanisms that regulate fatty acid uptake, for different depots. Therefore, these differing mechanisms may also impact the distribution of body fat.

References:

http://diabetes.diabetesjournals.org/cgi/content/full/56/10/2589

Lipids In Energy Storage

Lipids are small water-insoluble biomolecules generally containing fatty acids, sterols, or isoprenoid compounds . There are a variety of lipids and each participates in different metabolism processes uniquely. Lipids are used as energy storage via fatty acids. Fatty acids are composed of carboxylic acids attached to long chains of hydrocarbons. These are carbons that can range from 4 to 36 carbons. Fatty acids can be saturated, monounsaturated or polyunsaturated depending on the number of double bonds attached at the hydrocarbon skeleton. For example, saturated Lauric (n-Dodecnoic) acid exists in the laurel plant has a 12 carbon skeleton (CH3(CH2)10COOH) with a 12:0 ratio of carbon to double bond on its hydrocarbon chain.

Ball & stick model of Triglyceride

Unsaturated fatty acids such as Palmitoleic acid (cis-9-Hexadecenoic acid) and Oleic acid (cis-9-Octadecenic acid) has a single double bond between the 8 and 9 carbon on its hydrocarbon skeleton. Polyunsaturated fatty acids such as Arachidonic acid (cis-, cis-, cis-, cis-5,6,11,14- Icosatetraenoic acid) contained 4 double bonds on its hydrocarbon skeleton.

The most common type of fatty acid that is use for energy storage is in form of neutral fats. Neutral fats are the simplest type of lipids and are formed by three ester linkages of hydrocarbons to a glycerol otherwise known as triacylglycerols. These fats made up common foods such as butter and olive oil.

These neutral fats are efficient source energy storage because it is fully reduced and can be stored anhydrously. When it is fully reduced, these fatty acids are full of electrons which participate in a process called beta-Oxidation to produce acetyl CoA which can then integrated into the glycolysis and Citric Acid Cycle to from energy in form of ATP.

Image 2: Integration of beta-oxidation to other pathways[[1]]

Peer-Review Articles

COORDINATED REGULATION OF HORMONE-SENSITIVE LIPASE AND LIPOPROTEIN LIPASE IN HUMAN ADIPOSE TISSUE IN VIVO: IMPLICATIONS FOR THE CONTROL OF FAT STORAGE AND FAT MOBILIZATION.[[2]]

What is the main purpose of this article? This article implicates on the important of regulation in two different lipase enzymes for forming fatty acids.

Terms:

White adipocytes(White fat cells) - Also known as Unilocular Cells contain a large lipid droplet surrounded by a ring of cytoplasm. These fats are stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesterol ester.

Function: secrete resistin, adiponectin, and leptin.

Endothelium - A layer of flat cells lining the closed internal spaces of the body such as the inside of blood vessels and lymphatic vessels (that convey the lymph, a milky fluid) and the heart.

Lipogenesis - The process by which glucose is converted to fatty acids, which are subsequently esterified to glycerol to form the triacylglycerols that are packaged in VLDL and secreted from the liver.

Lipoproteins - Any member of a group of substances containing both lipid (fat) and protein. The lipoproteins in blood plasma have been intensively studied because they are the mode of transport for cholesterol. (Online Encyclopedia Britannica)

Non-esterified fatty acids (NEFA) - The fraction of plasma fatty acids not in the form of glycerol esters. In other words, it is free fatty acids floating in the blood.

How is this article related to what we’ve learned so far in Metabolism? In our study of metabolism of fatty acids as an energy storage source, regulation and control of enzyme is crucial in the amount of energy making and energy storing. This article studied the regulation of Lipoprotein Lipase (LPL) and Hormone-Sensitive Lipase (HSL) regarding to fat deposition and mobilization of triacylglycerol in white fat cells . Control of LPL allows the activation and inactivation of fat storing and releasing in adipose tissues. Similarly the controls of HSL allow mobilization of fatty acids to other pathways for synthesis. From what we know about energy storage from fats, a fatty acid must first be activated in the cytosol in which it enters the mitochondria via carnitine shuttle. In the mitochondria, beta-oxidation of the fatty acid occurs to make acetyl coenzyme A for ATP synthesis. Insulin is also mentioned in the article as a regulator hormone. Insulin inhibits beta-oxidation in the mitochondria but allow the process of fatty acid synthesis to occur. When the body is in need of energy, or lack of glucose, the body induces Glucagon hormone to allow sugar synthesis by gluconeogenesis. The activation of Glucagon allow fatty acid to be activated in which can enter the mitochondria for acetyl CoA to be synthesize. The acetyl CoA in thus participates in ATP synthesis and storage.

INHIBITION OF MITOCHONDRIAL BETA-OXIDATION AS A MECHANISM OF HEPATOTOXICITY [[3]]

What is the purpose of this article? Integration of Information: The important of beta-oxidation in avoiding biological disfunction.

Terms:

Hepatotoxicity - The damage of liver by chemical produced in the body.

Hepatocytes - Majority of these cells are seen in the liver and mitochondria. These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances.

Steatosis - The process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and breakdown of triglyceride fat.

Translocation - The process of moving protein by a cell to other part of cell.

Ketogenesis - The break down of fatty acid to form ketone bodies.

How is this article relate to what we’ve learned so far it Metabolism? This article discusses the severity of internal biological damages that can occur if the fatty acid beta-oxidation is inhibited. As notes, beta-oxidation is crucial in the human because ATP metabolism by fatty acid yield most of the ATP in the body. In the body, triacylglycerol is broken down via beta-oxidation in the mitochondria to yield acetyl CoA, which can go into the Citric Acid Cycle to yield energy. Acetyl CoA is an important molecule in body, not only to yield ATP but allow for other processes such as the synthesis of ketone bodies for the heart. Inhibition of beta-oxidation can be acquired by genetics precursor or through drugs. These NEFA Diethylaminoethoxyhexestrol, perhexiline maleate and amiodarone are the common harmful drugs that postpone beta-oxidation in the body . These drugs are often used for coronary heart disease treatments. With beta-oxidation inhibited problematic consequences such as Microvesicular Steatosis, Mitochondrial Cytopathies, and various inborn errors arises. Pancreatic syndrome also occurs with such inhibition.

MEDIUM CHAIN FATTY ACID METABOLISM AND ENERGY EXPENDITURE: OBESITY TREATMENT IMPLICATIONS [[4]]

What is the purpose of this article? Compare and contrast energy storage and energy expenditure of medium chain fatty acids and long chain fatty acids metabolism.

Terms:

Long chain fatty acids - Fatty acids that have 14 or more carbon attach.

Medium chain fatty acids - Fatty acids that has 8-10 carbon.

Chylomicrons - Large lipoprotein particles that are created in the small intestine. Chylomicrons transport fatty acid through the blood and to the mitochrondria.

Thermogenesis - The process of production of heat in an organism.

Omega oxidation - A process similar to beta-oxidation but the oxidation involves the  carbon from the carboxyl group of the fatty acid (wikipedia).

Peroxisomal-oxidation - The process of converting hydrogen peroxide to oxygen and water before it can decompose to form the highly reactive hydroxyl radical.

How is this article relate to what we’ve learned so far it Metabolism? In this article, medium chain fatty acids of 8-10 carbon long increases activity of lipase and thus absorb to the intestine at a much faster rate than long chain fatty acids. Study indicated that medium chain fatty acids do not need a lipoprotein for transport but can transport straight to the mitochondria via portal circulation for beta-oxidation. In this paper, other oxidative process such as omega-oxidation and peroxisomal-oxidation occurs in the liver. As seen before, long chain fatty acid need some sort of transport to other organ through the blood. Most often with long chain fatty acids, a carnitine shuttle is required to get the fatty acid into the mitochondria to do beta-oxidation. With medium chain fatty acids, a shuttle is not needed. Energy intake and stored from medium chain fatty acids metabolism is much more sufficient than long chain fatty acids. Appoximately 13% more energy intake compare to long chain fatty acids (Papamandjaris, Macdougall, Jones, p. 1209). We see than medium chain fatty acids metabolism is more efficient in which the intake and storing of energy is greater than that of long chain fatty acids. The

Web Resources

Webpage Title : Fatty Acid Oxidation

URL : http://www.dentistry.leeds.ac.uk/biochem/thcme/fatty-acid-oxidation.html

What is the purpose of this site? Integration of lipids metabolism derivatives to other pathways for energy synthesis and energy storage.

Terms:

Lipoprotein lipase - LPL uses lipoprotein lipase to hydrolyze lipids.

Hormone-sensitive lipase - It functions to hydrolyze triacylglycerols from the lipid droplet, freeing fatty acids and glycerols. (Wikipedia).

cAMP - A secondary messenger used for signal transduction.

Beta-adrenergic receptor - Any of various cell membrane receptors that can bind with epinephrine and related substances that activate or block the actions of cells containing such receptors. These cells initiate physiological responses such as increasing the rate and force of contraction of the heart as well as relaxing bronchial and vascular smooth muscle (the free dictionary).

G-Proteins - Function as "molecular switches," alternating between an inactive guanosine diphosphate (GDP) and activate guanosine triphosphate (GTP) bound state, ultimately going on to regulate downstream cell processes (wikipedia).

How is this site relate to what we’ve learn in metabolism? This is a good site on all the pathways involve in fatty acid metabolism. These include beta-oxidation, regulation of pathways, ketogenesis, and clinical significance of fatty acids. We’ve have talked about all of these process and this site really focus on the details of each process. Another pathway that is shown on this site is the mobilization of fats in adipocytes induced by hormone-sensitive lipase. This path show how fats cells are converted into glycerol.

Website Title : WKU Bio 113-Lipids

URL : http://bioweb.wku.edu/courses/BIOL115/Wyatt/Biochem/Lipid/lipid1.htm

Terms:

Saturated Fatty Acid - A fatty acid with carbon chain that has no double bond characteristics.

Unsaturated Fatty Acid (mono and poly) - A fatty acid that contain at least one double bond (monounsaturated) or many double bonds (polyunsaturated) on its carbon chain.

Hydrophillic - The polar portion of the fatty acid. This is typically the carboxyl group portion of the fatty acid.

Hydrophobic - The non-polar portion of the fatty acid. This is typically the carbon chain portion of the fatty acid.

Triglycerides - A fatty acid with a glycerol backbone connect to three fatty acid. This is often known as ‘neutral fats’ and triglycerides store energy.

How is this site relate to what we’ve learn in metabolism? This site provides good information on neutral fats that involve in energy production and storage. In metabolism, we learned that fatty acids are a good source of energy because it is fully reduced and can be stored anhydrously. This site shows the differences in saturated and unsaturated fatty acid and reasons that makes triglycerides a energy storage molecule.

Webpage Title : Mobilization and Cellular Uptake of Stored Fats (Triacylglycerols)with Animation- PharmaXChange.info

URL : http://pharmaxchange.info/press/2013/10/mobilization-and-cellular-uptake-of-stored-fats-triacylglycerols-with-animation/

What is the purpose of this site? Contains important information on the mobilization and cellular uptake of fats and fatty acids.

Terms:

Lipid Droplets Fatty acids and fats are stored in adipose tissue within lipid droplets which have a structure with a core of sterols and triacylglycerols surrounded by a layer of phospholipids. The phospholipid layer is surrounded by hydrophobic membrane proteins known as perilipins.

How is this site relate to what we’ve learn in metabolism? This is a good page covering the mobilization and cellular uptake of fatty acids and it has a useful animation which can help visualize the process.

Website Title : Pathways

URL : http://ull.chemistry.uakron.edu/Pathways/index.html

What is the purpose of this site? Provide a flow chart of fatty acid synthesis and its connection to all the metabolic pathways in the body to yield energy. This site is a good source when studying for Metabolism.

Terms:

Transamination - The reaction between an amino acid and an alpha-keto acid. The amino group is transferred from the former to the latter; this results in the amino acid being converted to the corresponding α-keto acid, while the reactant α-keto acid is converted to the corresponding amino acid (if the amino group is removed from an amino acid, an α-keto acid is left behind (wikipedia).

Deamination - The removal of the amino group on a molecule (wikipedia).

How is this site relate to what we’ve learn in metabolism? The importance of integration of pathways is crucial in learning metabolism. By integrating the pathways of fatty acid synthesis to fatty acid oxidation shows how energy is yield and stored.

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KEGG Pathway and MetaCyc

Anabolic

Oxidative Phosphorylation : http://www.genome.ad.jp/kegg/pathway/map/map00190.html

Fatty Acid Synthesis : http://www.genome.ad.jp/kegg/pathway/map/map00061.html

Fatty acid elongation in mitochondria : http://www.genome.ad.jp/kegg/pathway/map/map00062.html

Catabolic

Synthesis and degradation of ketone bodies : http://www.genome.ad.jp/kegg/pathway/map/map00072.html

Metabolism

Fatty acid metabolism : http://www.genome.ad.jp/kegg/pathway/map/map00071.html

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References

[1] Nelson, L. D.; Cox, M. M., Lipids. In Lehninger Principles of Biochemistry, 4 ed.; W.H. Freeman and Company: New York, 2005.

[2] Frayn, K. N.; Coppack, S. W.; Fielding, B. A.; Humphreys, S. M., Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: Implications for the control of fat storage and fat mobilization. Advances in Enzyme Regulation 1995, 35, 163-178.

[3] Fromenty, B.; Pessayre, D., Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacology & Therapeutics 1995, 67, (1), 101-154.

[4] Papamandjaris, A. A.; Macdougall, D. E.; Jones, P. J. H., Medium chain fatty acid metabolism and energy expenditure: Obesity treatment implications. Life Sciences 1998, 62, (14), 1203-1215.