The role of fatty acid β-oxidation in lymphangiogenesis – A Spotlight

Wong et al. explore the relationship between acetyl-CoA production from fatty acid beta-oxidation (FAO) and endothelial cell differentiation in the lymphatic system. Acetyl-CoA is a common metabolic intermediate across cellular pathways in metabolism. This metabolite is generated from a variety of nutrients, such as glucose or fatty acids, and depending on the cellular designation it may have a variety of ultimate destinations. Notably, acetyl-CoA is involved in energy generation via the TCA cycle and histone acetylation for use in gene control. Wong et al. visited the role of FAO in generating acetyl-CoA in endothelial cells for histone acetylation required for cell differentiation involved in lymphangiogenesis (Wong et al., 2016).

The lymphatic system is crucial to the vertebrate adaptive immune system, dietary lipid absorption, and interstitial fluid. When this system is disrupted, diseases such as cancer metastasis, lymphedema, and organ transplant rejection (Choi et al., 2012) may arise. The normal functioning lymphatic system consists in part of endothelial lymphatic cells (LECs) and venous lymphatic cells (VECs), which become differentiated through extracellular cues like VEGF-C.

FAO occurs within the mitochondrial matrix, and therefore the first steps of this process involved transporting fatty acids linked to acetyl-CoA (fatty acyl-CoA) across the inner mitochondrial membrane. The carnitine shuttle is the main process by which fatty acyl-CoA traverses this membrane, by converting the fatty acyl-CoA into fatty acyl-carnitine. Carnitine palmitoyl-transferase 1 (CPT1) is located within the outer mitochondrial membrane and aids fatty acids going into the matrix, where CPT2 reconstituted fatty acyl-carnitine to fatty acyl-CoA. FAO converts this substrate into acetyl-CoA, which may be used in either the TCA cycle to regenerate citrate or exported to the cytosol for other uses. CPT1 exists as three isoforms in mammals as CPT1A, CPT1B, and CPT1C, which are located in differing tissue concentrations. Wong et al. noticed increased rates of FAO and concentrations of CPT1A in LECs opposed to VECs and hypothesized CPT1A may be required for lymphangiogenesis (Wong et al., 2016). Prox1 induces CPT1A expression in cells. This hypothesis is supported by evidence that blocking CPT1A function impairs lymphangiogenesis.

Due to the myriad of functions of acetyl-CoA in cells, the authors investigated the destiny of those produced in LECs. Authors demonstrated FAO activity in LECs through the use of a [9,10-H] palmitate tracer. To elucidate whether acetyl-CoA was being oxidized as fuel to generate ATP (Ookhtens and Baker, 1983), FAO was blocked in LECs but no change in cellular energetics was detected. Despite this experiment, it is unclear whether or not the cell was capable of compensating for the loss of energy from fatty acid oxidation through other, unclear, means. Acetyl-CoA may also be consumed during fatty acid synthesis or within TCA intermediates as they are used to build other molecules such as nucleotides. Despite the chemistry of the TCA cycle permitting such expenditure of acetyl-CoA, it does not add any net contribution to the products.

Acetyl-CoA can be used in histone acetylation, which is of most interest to the authors. Histone acetylation plays a role in the regulation of protein function and synthesis, as well as a role in epigenetic gene regulation. Acetylated histones typically result in the increased activity of nearby genes as the positively charged lysine residue on the histone is balanced by the acetyl group, acetylation also is recognized by other regulatory proteins. Acetylation of histones may be based on relative acetyl-CoA concentrations within the cell (Kinnaird et al., 2016). Authors find FAO generated acetyl-CoA is associated with epigenetic regulation of lymphangiogenesis.

Authors find that changing CPT1A activity modulates expression of LEC markers such as VEGFR3. Wong et al. conclude differentiation of LECs is dependent on sufficient supplies of acetyl-CoA and histone acetylation of associated genes. Histone acetylation of LEC genes are negatively associated with loss of CPT1A function (Wong et al., 2016), but exogenously added acetate returns the cell to normal display of lymphangiogenesis despite CPT1A inhibition. Prox1 is also found to associate with p300 histone acetyltransferase to enhance H3K9 acetylation of LEC genes.

Epigenetic effects of acetyl-CoA create an interesting precedent for understanding various normal and disease physiologies. Understanding the effect of cell type on the destination and effects of this metabolite will provide insight into how metabolic pathways generate regulatory molecules that interact with development.




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Kinnaird, A., Zhao, S., Wellen, K.E., and Michelakis,
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Ookhtens, M., and Baker, N. (1983). Am. J. Physiol.
244, R84–R92.

Wong, B.W., Wang, X., Zecchin, A., Thienpont, B.,
Cornelissen, I., Kalucka, J., Garcia-Caballero, M.,
Missiaen, R., Huang, H., Bruning, U., et al. (2016).

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