Metabolomics/Metabolites/Lipids

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Lipids

1. Energy Storage
2. Membrane Lipids
3. Steroids

Peer-Reviewed Article #1:

Lipid metabolome-wide effects of the PPAR{gamma} agonist rosiglitazone

Journal of Lipid Research, Vol. 43, 1809-1817, November 2002'"

Reviewer: Monique Harris

Related Image(s)

The image above is one of the Type 2 diabetes drug rosiglitazone shown in both orientations.

Main Focus

The main focus of this paper was to observe the effect of Type 2 diabetes drug, rosiglitazone has on the liver and its’ structural lipid metabolome. The experimental phase was done using male mice that had Type 2 diabetes and were obese. The peroxisome proliferator-activated receptor γ or PPARγ was specifically observed for changes in process.

New Terms

Hyperlipidemia

a disorder of high cholesterol and high blood triglycerides that is passed down through families. (source: http://www.nlm.nih.gov/medlineplus/ency/article/000396.htm)

Adipogenesis

the production of fat, either fatty degeneration or fatty infiltration; also applied to the normal deposition of fat or to the conversion of carbohydrate or protein to fat. (source: http://www.mondofacto.com/facts/dictionary?adipogenesis)

Hepatotoxicity

liver damage that is done by chemicals either by medication or laboratory testing. (source: http://en.wikipedia.org/wiki/Hepatotoxicity)

Steatosis

a fatty liver. (source: http://emedicine.medscape.com/article/175472-overview)

Hyperinsulinemia

the presence of excess insulin in the blood. (source: http://dictionary.reference.com/browse/hyperinsulinemia)

Inguinal

relating to, or situated in the region of the groin or in either of the lowest lateral regions of the abdomen. (source: http://www.merriam-webster.com/dictionary/inguinal)

Hyperglycemia

an abnormally increased content of glucose in the blood. (source: http://medical-dictionary.thefreedictionary.com/hyperglycemia)

Lipogenesis

is the process by which simple sugars such as glucose are converted to fatty acids. (source: http://en.wikipedia.org/wiki/Lipogenesis)

Modulate

to adjust or adapt to a certain proportion; regulate or temper. (source: http://www.thefreedictionary.com/modulate)

Plasmalogen

a group of glycerol-based phospholipids in which a fatty acid group is replaced by a fatty aldehyde. (source: http://www.answers.com/topic/plasmalogen)

Summary

The quantitative and comprehensive analysis of the structural lipid metabolome was applied to gain an understanding of the effect that the Type 2 diabetes drug rosiglitazone has on the liver metabolism. Thiazolidinediones (TZDs) are potent therapeutic agents that have proven successful in the treatment of Type 2 diabetes in rodent models and in humans. TZDs include troglitazone, pioglitazone, and rosiglitazone. The peroxisome proliferator-activated receptor γ or PPARγ is supposed to have a high sensitivity to TZDs and after activation, is supposed to improve insulin sensitivity.

However, TZD usage is accompanied by increased adipogenesis and lipid accumulation in tissues. There is question if the benefits to circulating lipid concentration can be disassociated from metabolic side effects including hepatic lipid accumulation. For the mice that were used, some had diabesity genes that led to early onset obesity leading to a progressively more sever hyperinsulinemia. TZD treatment was done one the liver metabolism and rosiglitazone was more potent antidiabetic TZD than troglitazone in early studies.

It was revealed that actions of rosiglitazone and putatively PPARγ had key targets on lipid metabolism. Two groups of mice, one control and one experimental were used in the experiment. The mice were a cross of Nonobese Nondiabetic Zealand Obese (NZO/HILt) and Nonobese Nondiabetic (NON/LT) strains. They were feed for 4 weeks and then euthanized at which point blood, heart tissue, liver tissue and inguinal adipose were collected, weighed and frozen for analysis.

Gene expression data was obtained by measuring the fluorescence intensity for each PCR reaction using the system software and was analyzed in EXCEL®. Lipids from plasma and tissues were extracted and prepared thin-layer chromatography to analysis. Also fatty acid methyl esters were collected and ran by capillary gas chromatography using a gas chromatograph. Quantitative data was visualized suing the Lipomic Surveyor™ software system which made a heat-map graph of the difference between control and treated mice. The heat map displayed the increase in each metabolite in rosiglitazone-treated mice relative to control mice by the intensity of the brightness.

After 4 weeks of rosiglitazone treatment, diabetic hyperglycemia was completely reversed. That reversal also was accompanied by decline in plasma concentrations of insulin, leptin, triacylglyerides and cholesterol. The rosiglitazone treated mice had gained more body weight that the control mice, especially in the inguinal fat, heart and liver areas. Liver lipid metabolism results included a substantial accumulation of triacylglyerides and the inhibition of normal liver-plasma lipid exchange. Heart lipid metabolism results included the increased biosynthesis of n-7 fatty acids and increased concentration of triacylglyerides and free fatty acids of plasma. The hearts of the rosiglitazone treated mice were significantly enriched with cardiolipin however concentrations of plasmalogens were lower. This was consistent with a decrease peroxisome synthesis of lipids within hearts of treated mice. Adipose lipid metabolism results included a decrease in triacylglyerides content but an increase in fatty acids. The treated mice had an n-7 and n-3 fatty acid accumulation while have a depletion of n-9 fatty acids. The plasmalogen lipids in inguinal fat phospholipids were depleted by the treatment.

Overall the rosiglitazone treatment is often accompanied by weight gain. Increased synthesis of fatty acids occurred as well as an upregualtion of expression of genes associated with adipogenesis and fatty acid synthesis was found. Palmitoleic acid was an excellent indicator of the increased synthesis of fatty acids in both the live and adipose tissue. Rosiglitazone, a PPARγ agonist has an inhibitory effect on lipid biosynthesis in the peroxisome. It induced hyperlipidemia by disruption the mobilization of liver lipids into plasma and induced de novo fatty acid synthesis. Diminished the biosynthesis of lipids synthesized within the peroxisome and had substantial effect on the heart cardiolipin and free fatty acid metabolism. Lastly, it exerted tissue specific effects on lipid metabolism.

It is hypothesized that the mice used in the experiment might have had underlying defects that rendered them sensitive to steatosis inducing effect to TZDs. Over all it should be noted that mice metabolism is very distinctly different than human lipid metabolism and directly application needs to be tested.

Relevance to a Traditional Metabolism Course

The topic of metabolome wide effects is a topic that could be easily related to a metabolism course. The paper mentions some pathways that are affected and could be further studied to see the complete involvement of the Type 2 diabetes drug rosiglitazone. One pathway is the electron transport chain. It is known that cardiolipin composition and content is important to the efficiency of electron transport. An increase in cardiolipin increased electron transport efficiency as well as decreased electron leakage. Also, there were two major lipid structures studied that are produce with in the peroxisome and these fatty acids as well as plasmalogen lipids are involved with the dihydroxyacetone phosphate biosynthetic pathway. Lastly, the study looked at the conversation of polyunsaturated rich phospholipids to triacylglyerides via a phospholipase C pathway.