Lipogenesis

Lipogenesis

Lipogenesis is the process by which simple sugars such as glucose are converted to fatty acids, which are subsequently esterified with glycerol to form the triacylglycerols that are packaged in VLDL and secreted from the liver.

Lipogenesis encompasses the processes of fatty acid synthesis and subsequent triglyceride synthesis.

Lipogenesis starts with acetyl-CoA and builds up by the addition of two carbons units. The synthesis occurs in the cytoplasm in contrast to the degradation (oxidation) which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase [cite web | author=Elmhurst College | title= Lipogenesis |url=http://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html |accessdate=2007-12-22 ] .

Control and Regulation

Insulin is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood sugar levels. Thus a large insulin level is associated with the fed state. As one might expect therefore, it increases the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in three main ways.

Malonyl-coenzyme A

In fat synthesis, the enzyme pyruvate dehydrogenase, which forms acetyl-coA, and also acetyl-coA carboxylase which forms malonyl-coA are obvious control points. These are activated by insulin. This leads to an overall increase in the levels of malonyl-coenzyme A, which is the substrate required for fat synthesis. Thus, the flux down storage pathway is increased when there is sufficient glucose in the 'fed' state.

Pyruvate dehydrogenase dephosphorylation

Pyruvate dehyrdrogenase dephosphorylation is increased with the release of insulin. The dephosphorylated form is more active.

This mechanism is not clear, as insulin binds to extra-cellular parts of protein receptors and pyruvate dehydrogenase is found in the mitochondrial matrix. There must be some sort of secondary messenger process.

This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-coA. Increased levels of acetyl-coA will not only increase the flux through the fat synthesis pathway, but also the citric acid cycle.

Acetyl-coA carboxylase

Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation. Glucagon has an antagonistic effect and increases phosphorylation, therefore inhibiting ACC, and slowing fat synthesis. This inhibition mechanism is thought to be something to do with ACC-dependent protein kinase.

Affecting ACC affects the rate of acetyl-coA conversion to malonyl-coA. Malonyl-coA increae pushes the equilibrium over to increase production of fatty acids through biosynthesis.

AMP activated protein kinase acts as a measure of the ATP needs of a cell and acts to phosphorylse ACC. When ATP is depleted there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.

ACC is also activated by citrate. This means that when there is abundant acetyl-coA in the cell cytoplasm for fat synthesis it proceeds at an appropriate rate.

Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's influence on lipogenic enzyme genes, can induce the gene products for Liver pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high blood glucose levels and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also involved in cholesterol metabolism. Work from Howard Towle, Catherine Postic, and K. Uyeda can be referenced for ChREBP/Mlx effects described above.

References

External links

*http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1083868
*http://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html


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