Fatty Acid Metabolism
July 6, 2010
Edited by Roderick Capaldi, D.Phil.
Past issues are available for review in the archives.
Table of Contents
I. INTRODUCTION
II. USEFUL REVIEWS
III. ACETYLATION OF PGC1S IS A KEY CONTROL ELEMENT IN FATTY ACID METABOLISM
IV. PPARS REGULATE SIRT 1 EXPRESSION
V. MANY OF THE FATTY ACID OXIDATION ENZYMES ARE ACETYLATED, WITH DEACETYLATION CATALYZED BY SIRTUINS
VI. FATTY ACID METABOLISM IS ALSO CONTROLLED BY MICRO-RNAS
VII. IS THERE A LINK BETWEEN FATTY ACID OXIDATION AND APOPTOSIS?
VIII. MONITORING CHANGES IN FATTY ACID METABOLISM; FOLLOW THE PROTEINS
I. INTRODUCTION
Fatty acid metabolism is controlled at several levels including at the transcriptional level e.g. via the PPAR and PGC1 transcription factors, and also, through post translational modification of key enzymes in the different pathways e.g. the phosphorylation of ACC which is the key control step in fatty acid synthesis.
Recently, it has become clear that acetylation of key proteins is also involved in regulating fatty acid metabolism. The acetylases involved are diverse and still poorly defined. De-acetylation is catalysed predominantly by the sirtuins of which there are at least 7 in mammalian cells, four of which, SIRT1,2,6 and 7 are cytosolic and/or nuclear, and three of which, 3,4 and 5 are localized to mitochondria.
II. USEFUL REVIEWS
1. Zhao S, et al. Regulation of cellular metabolism by protein lysine acetylation. Science. 2010 Feb 19;327(5968):1000-4.
2. Schwer B & Verdin E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 2008 Feb;7(2):104-12.
3. Feige JN, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008 Nov;8(5):347-58.
4. Finkel T, et al. Recent progress in the biology and physiology of sirtuins. Nature. 2009 Jul 30;460(7255):587-91.
III. ACETYLATION OF PGC1S IS A KEY CONTROL ELEMENT IN FATTY ACID METABOLISM
Among the many targets of Sirt1 is PGC1beta. Recent studies from the Puigserver lab have now established that the functioning of PGC1s is controlled by acetylation. In one study they show that 10 sites distributed along PGC1beta are acetylated by the acetylase GCN5 (general control of amino acid synthesis) and deacetylated by Sirt1. Preventing this acetylation increases the transcriptional activity of PGC1beta and thereby increases levels of MCAD and other fatty acid oxidation enzymes.
5. Kelly TJ, et al. GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation. J Biol Chem. 2009 Jul 24;284(30):19945-52.
6. Dominy JE Jr, et al. Nutrient-dependent regulation of PGC-1alpha's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim Biophys Acta. 2009 Dec 11. (Epub ahead of print.)
IV. PPARS REGULATE SIRT 1 EXPRESSION
In an interesting recent publication, Okazaki et al. add to the complexity of overall control of fatty acid metabolism by showing that transcription of the Sirt1 gene is itself controlled by fatty acid metabolism in as much as it is regulated by PPAR beta/delta indirectly through Sp1.
7. Okazaki M, et al. PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. Endocr J. 2010 Feb 17. (Epub ahead of print.)
V. MANY OF THE FATTY ACID OXIDATION ENZYMES ARE ACETYLATED, WITH DEACETYLATION CATALYZED BY SIRTUINS
Schwer et al. have recently described an extensive proteomic study of de-acetylation of mitochondrial enzymes by calorie restriction, the implication being that those affected are targets of the mitochondrial sirtuins. They observe changes in mitochondrial enzymes in several pathways, including the fatty acid synthesis enzyme ACAA2, along with ETF, ETF dehydrogenase, PCCA, and TFP (HADHA&B;), all enzymes involved in fatty acid oxidation within the organelle.
8. Schwer B, et al. Calorie restriction alters mitochondrial protein acetylation. Aging Cell. 2009 Sep;8(5):604-6
The acetylation of ACAA2 (mitochondrial form of the enzyme) has been known for some time. Very recently, evidence has been presented that Sirt 3, one of the mitochondrially-located sirtuins, binds to and modulates LCAD This study shows that LCAD activity is inhibited by acetylation of the enzyme.
9. Hirschey MD, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010 Mar 4;464(7285):121-5.
VI. FATTY ACID METABOLISM IS ALSO CONTROLLED BY MICRO-RNAS
Evidence is now accumulating for involvement of microRNAs in control of the genes for lipid metabolism Relevant papers are listed below. In one it is shown that microRNA miR-696 regulates PGC1alpha. In a second recent study, Iliopoulos et al. transfected HepG2 cells with anti-sense miR-370 or miR-122 and observed down-regulation of the transcription factor SREBP1c (sterol regulatory element binding protein 1c) along with the enzymes DGAT2, FAS and ACC1, each of which are important in regulating fatty acid or triglycerol biosynthesis.
10. Aoi W, et al. The microRNA miR-696 regulates PGC1alpha in mouse skeletal muscle in response to physical activity. Am J Physiol Endocrinol Metab. 2010 Jan 19. (Epub ahead of print.)
11. Iliopoulos D, et al. MicroRNA-370 controls the expression of microRNA-122 and Cpt1{alpha} and affects lipid metabolism. J Lipid Res. 2010 Feb 2. (Epub ahead of print.)
VII. IS THERE A LINK BETWEEN FATTY ACID OXIDATION AND APOPTOSIS?
There is reason to believe that a link should exist between fatty acid oxidation and apoptosis and that this could be exploited in treatment of cancers. It is now well accepted that cell metabolism in cancer is altered in favor of fatty acid synthesis over FAO as a part of the so-called Warburg effect (in which cancer cells generate most of their energy by glycolysis and there is reprogramming of both glucose and fat utilization).
Recent evidence suggests a more direct link between FAO inhibition in cancer and cell death involving mitochondria. In a recent study Samudio et al. showed that drug-induced inhibition of FAO limited proliferation and sensitized leukemia cells to apoptosis by a compound known to release Bak from Bcl-2 proteins at the mitochondrial surface. Further, they showed that inhibiting the fatty acid synthase also sensitized cells to apoptosis inducers. This new work supports earlier evidence that the pro-apoptotic protein tBid can regulate FAO by direct interaction and inhibition of carnitine palmitoyltransferase 1.
12. Samudio I, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010 Jan;120(1):142-56.
13. Giordano A, et al. tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1. Cell Death Differ. 2005 Jun;12(6):603-13.
VIII. MONITORING CHANGES IN FATTY ACID METABOLISM; FOLLOW THE PROTEINS
The studies above are an important reminder that in fatty acid metabolism, as in most events in cells and tissues, the ultimate description of the physiology requires a direct analysis of the protein components, not only measurement of levels of, or changes in, mRNA levels. Further, changes in fatty acid metabolism cannot be fully rationalized without consideration of other cellular pathways and events including apoptosis.
Proteomics is progressing both in terms of extent of coverage of the proteins present in complex samples, in quantitative analysis, in identification of post-translational modifications and in ability to be conducted in relatively high throughput. However the availability of the method is limited by the cost of equipment and the user skill needed to obtain reproducible and interpretable data, and there remains an important place for antibody based methods such as ELISA assays to monitor levels of and changes to proteins. The broad set of monoclonal antibodies being released now by MitoSciences will aid greatly in evaluating the changes in fatty acid metabolism that define many diseases including diabetes, metabolic syndrome, obesity and cancer.
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