How is fatty acid oxidation regulation

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Trace holmium assisting delaminated OMS-2 catalysts for total toluene oxidation at low temperature. While malonyl-CoA is used as a substrate for fatty acid biosynthesis, malonyl-CoA is also a potent inhibitor of mitochondrial fatty acid uptake secondary to inhibition of CPT1 Figure 2 [1].

There are two forms of ACC, a kDa ACC1 isoform, which is highly expressed in the liver and adipose tissue, and a kDa ACC2 isoform which is more specific to highly metabolic organs such as skeletal muscle and the heart [1].

Next, enoyl-CoA hydratase removes the double bond just formed, in the process of adding a hydroxyl group to the third carbon down from the CoA group and a hydrogen on the second carbon down from the CoA group. Hydroxyacyl-CoA dehydrogenase removes the hydrogen in the hydroxyl group just attached and in the process produces a NADH.

In the final step, ketoacyl-CoA thiolase attaches a CoA group on to the third carbon down from the CoA group resulting in the formation of two molecules, an acetyl-CoA and an acyl-CoA that is two carbons shorter.

Long-term regulation of ACC depends on regulation of its gene expression. For example, Adam et al. Generally, the level of malonyl-CoA is decreased when MCD activity is increased, resulting in an elevated rate of fatty acid oxidation. However, MCD appears to be primarily regulated by transcriptional means discussed later. Mitochondrial carnitine palmitoyl transferase CPT :. The CPT isoform, CPT1, resides on the inner surface of the outer mitochondrial membrane and is a major site of regulation of mitochondrial fatty acid uptake [1].

Mammals express three isoforms of CPT1, which are encoded by different genes. The number of acetyl-CoA produced depends upon the carbon length of the fatty acid being oxidized. For example, there is a very-long-chain acyl-CoA dehydrogenase, a long-chain acyl-CoA dehydrogenase, a medium-chain acyl-CoA dehydrogenase, and a short-chain acyl-CoA dehydrogenase.

Interestingly, the enoyl-CoA hydratase, hydroxyacyl-CoA dehydrogenase, and ketoacyl-CoA isoforms specific for long-chain fatty acids form an enzyme complex on the inner mitochondrial membrane. Regulation can occur at the level of fatty acid entry into the cell. Regulation also occurs via the regulation of the levels of acetyl-CoA and malonyl-CoA. While propionyl-CoA could be metabolized through alternative pathways, it is primarily metabolized in the cell to succinyl-CoA by three enzymes propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase [].

Compared to even-numbered fatty acids, odd-numbered fatty acids occur infrequently in nature [15]. The two auxiliary enzymes, enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase are necessary for the complete oxidation of unsaturated fatty acids [11].

A double bond on an even-numbered carbon requires both the auxiliary enzymes. Enoyl-CoA hydratase then acts on the acyl-CoA and the process resumes its normal order.

In animals, peroxisomes are believed to be important in the initial breakdown of very-long-chain fatty acids and methyl branched fatty acids [11]. The enzymes involved in fatty acid oxidation in peroxisomes are different from mitochondria. The H 2 O 2 is broken down to water by catalase. There are a number of transcription factors that regulate the expression of these proteins.

The genes regulated by each of the PPARs vary between tissue types. PPAR isoforms are also differentially expressed between tissue types [18]. This process involves many steps that are regulated at the transcriptional and post-transcriptional level. Figure 1. Fatty acid esterification to acyl-CoA: A fatty acid must be converted to fatty acyl-CoA in order for it to enter the mitochondria and be oxidized [1]. Figure 2. Mitochondrial carnitine palmitoyl transferase CPT : The CPT isoform, CPT1, resides on the inner surface of the outer mitochondrial membrane and is a major site of regulation of mitochondrial fatty acid uptake [1].

Figure 3. References Lopaschuk, G. Myocardial fatty acid metabolism in health and disease. Blood cells are formed in the bone marrow where they originate from haematopoietic stem cells HSC. In AML, HSCs undergo genetic mutations that result in ineffective haematopoiesis and dysfunctional blood cells due to impaired differentiation Shih et al.

These leukaemia stem cells show spontaneous apoptosis in vitro but increased proliferation in vivo Lane et al. AML cells can be characterised by aberrant genetic and epigenetic changes that distinguish them from healthy cells Metzeler et al. Otto Warburg proposed that cancer cells exhibit increased glycolysis in the presence of oxygen Warburg effect , thereby providing the cells with a more readily accessible source of ATP Warburg, Initially, this idea led researchers to think of cancer in terms of metabolic dysfunction due to mitochondrial injury.

Instead, what is becoming evident is that metabolic plasticity may be a cellular adaption to increased energy demands of proliferating cells in a harsh tumour microenvironment in which there may be limited nutrient and oxygen supply.

These unfavourable conditions require cancer cells to modulate their metabolism to one that promotes survival and proliferation, which in turn may lead to drug resistance Ma et al. Dysregulation of fatty acid FA metabolism has been implicated in a variety of diseases and a prominent role in cancer is emerging.

FA synthesis is required for anabolic reactions such as membrane biosynthesis and generation of signalling molecules. This review endeavours to highlight the changes in lipid metabolism that distinguish malignant AML cells from normal, healthy cells.

Firstly, to give some background, we provide a summary of anabolic and catabolic FA metabolism and an overview of key transcriptional regulators. We also present and discuss relevant epigenetic regulators and the reciprocal effects of FA metabolism on epigenetic mechanisms. Lipids originate from dietary sources or are generated by de novo FA biosynthesis occurring mainly in the liver and adipose tissue reviewed in Salati and Goodridge, Acetyl-CoA is converted within the tricarboxylic acid TCA cycle to citrate and subsequently transported into the cytoplasm by the citrate transporter.

In the cytoplasm, citrate is cleaved by citrate lyase regenerating acetyl-CoA that can then be used for FA synthesis. The remaining steps are catalyzed by the FA synthase FAS complex, which leads to a series of reactions until the carbon FA palmitic acid, is synthesised.

Further elongation and desaturation takes place at the endoplasmatic reticulum membrane Salati and Goodridge, Figure 1. A schematic representation of fatty acid FA metabolism.

In the cytosol, FAs can either be stored in lipid droplets or undergo enzymatic conversion to FA-acyl-CoA that can enter the mitochondria via the carnitine palmitoyltransferases 1 and 2 CPT1, CPT2 transporters, located on the outer and inner mitochondrial membranes, respectively.

The activation of CPT1 is a survival signal and inhibits the oligomerisation of the pro-apoptotic Bcl-2 family proteins, Bak, and Bax. Acetyl-CoA is released and enters the tricarboxylic acid cycle TCA , where it is oxidised for citrate production.

Citrate is transported to the cytosol where it is converted to acetyl-CoA. In addition to the short-term and transient regulation through post-translational modifications, long-term mechanisms include changes in expression of genes encoding key FA synthesis enzymes and occur in response to dietary factors.

In particular, CD36 plays an important role in the regulation of FA uptake due to its ability to translocate between intracellular endosomes and the plasma membrane. This intracellular translocation is dependent on FA availability, the energy status of the cell Luiken et al. Acyl-CoA is transported into the mitochondria by the carnitine palmitoyltransferases, CPT1 and CPT2, that are located at the outer and inner mitochondrial membranes, respectively McGarry et al.

Both anabolic and catabolic processes of FA metabolism are under the control of transcription factors TFs Figure 2. Figure 2. Depicted are the main transcription factors involved in fatty acid FA synthesis and FA oxidation. A In response to high glucose concentrations, carbohydrate responsive element-binding protein ChREBP is transported to the nucleus.

SREBP is cleaved to produce its active transcription factor form, a process that is inhibited by high levels of cholesterol. These events result in up-regulation of FA oxidation by increasing expression of FA transporters and rate-limiting enzymes CD36, ACC2, acyl-CoA oxidase and by increasing overall mitochondrial biogenesis.

Anabolic regulators of FA metabolism play a role in countering the effects of higher oxidation in times of plentiful nutrient supply by increasing FA synthesis and storage. A build up of FAs or cholesterol can be toxic to cells and so feedback loops are in place to control intracellular levels.

SREBPs are bound to the endoplasmic reticulum from where they translocate to the nucleus in response to depleted intracellular FA or cholesterol levels Sakai et al. While TF-mediated regulation in metabolism is generally transient, epigenetic factors may confer prolonged alterations, which can be transmitted to the next generation. Chromatin modifications comprise the molecular basis of epigenetic mechanisms, of which DNA methylation is related with gene silencing reviewed in Wolffe and Matzke, , and histone acetylation is associated with gene transcription Marmorstein and Zhou, Diets rich in fat have been shown to affect chromatin accessibility of regulatory gene regions in rodents Leung et al.

Several studies in rodent offspring have shown that higher maternal dietary fat intake caused persistent DNA hypermethylation and down-regulation of the Fads2 gene, which encodes FA desaturase in FA synthesis Niculescu et al. Similar diet-induced epigenetic changes found in adult rodents could be reversed by decreasing fat intake Hoile et al.

Interestingly, the resulting decreased expression can be counteracted by maternal exercise, further highlighting the plasticity of FA metabolism Laker et al.

Acetyl-CoA is generated from glucose via glycolysis and is substrate for histone acetylation Takahashi et al. Indeed, high levels of glucose have been shown to increase histone acetylation Wellen and Thompson, , while a converse reduction in acetyl-CoA synthesis results in rapid histone deacetylation Takahashi et al.

In this way, acetyl-CoA is an important link between energy metabolism and chromatin regulation Rathmell and Newgard, ; Wellen and Thompson, FAs also affect acetyl-CoA levels and thus histone acetylation. On the one hand, de novo FA synthesis uses acetyl-CoA as substrate, and therefore competes with histone acetylation for the same acetyl-CoA pool. Lowering the rate of FA synthesis, by reducing ACC1 expression, increases global histone acetylation and gene expression Galdieri and Vancura, On the other hand, stimulating FA oxidation, and thereby increasing acetyl-CoA levels, leads to increased histone acetylation McDonnell et al.

In addition epigenetic factors may also act on non-chromatin substrates to regulate FA metabolism. Interestingly, metabolic enzymes can also more directly act to bring about changes in chromatin structure and gene transcription.

Further, it has been reported that almost all glycolytic enzymes are RNA-binding proteins, thereby linking metabolism and gene transcription Beckmann et al.

Overall there is complementary interplay between epigenetic regulation and FA metabolism that is mediated by dietary FAs directly altering methylation states and by the provision of acetyl-CoA for acetylation. It is now well accepted that epigenetic changes contribute to haematological cancers Pastore and Levine, During recent years links between epigenetic regulation and an altered FA metabolism have been emerging in AML.

Simultaneous up-regulation of lipolysis and dysregulation of lipogenesis has been speculated to be a potential hallmark of cancer cell metabolism Carracedo et al. Healthy haematopoietic and leukaemia stem cells have been traditionally identified by immunophenotyping cell markers Bennett et al. However, metabolic heterogeneity among these cell populations is becoming increasingly evident.

While we are just at the beginning of understanding the significance of metabolic changes in leukaemia, increased reliance on FAs as fuel is becoming apparent.

The bone marrow microenvironment provides nutrients and growth signals to both healthy HSCs and disease clones. The bone marrow is composed of an array of different cell types including adipocytes and mesenchymal stem cells and is the pertinent site of interest in leukaemia Medyouf, AML blasts undergo spontaneous apoptosis in vitro , but proliferate in vivo in the bone marrow Lane et al. Indeed, bone marrow adipocytes protect acute monocytic leukaemia cells by disrupting apoptosis.

Adipocytes also produce adipokines such as leptin and adiponectin, which modulate FA metabolism of nearby cells VanSaun, Overall, AML cells manage to take advantage of the robust growth-promoting environment of the bone marrow. However, due to the invasive nature of alloHCT and compounding risk factors of comorbidities, chemotherapies remain the preferred treatment options for elderly AML patients Ustun et al.

Recent studies have indicated that metabolic changes may confer drug resistance. High oxidative phosphorylation has been associated with cytarabine ara-C —resistance in leukaemia cells Farge et al.

Although Ara-C killed both resting and proliferating cancer cells, the remaining resistant cells were characterised by increased FA oxidation and up-regulated CD In another study, CDpositive leukaemia cells were shown to be relatively more drug-resistant to AraC in vivo and in vitro compared with CDnegative cells Ye et al.

This might explain why obesity is a leading risk factor for most cancers Lichtman, In the context of leukaemia, excess adipose tissue increases the risk of disease onset Naveiras et al. Coupled with these findings is the increased proportion of adipose tissue in the bone marrow as people age, which incidentally correlates with increased rates of disease incidence Stenderup et al.

Taken together, the accumulation of bone marrow adipose tissue and incidence of obesity represent probable risk factors for acquiring AML and subsequent therapy resistance. Based on these findings, efforts have been made to target FA metabolism as a therapeutic strategy. For instance, the FA uptake protein CD36 has been evaluated as a potential target. However, its toxicity in vivo deems SSO unsuitable for therapeutic use.

As an alternative strategy, inhibitory CDspecific antibodies increase sensitivity of chronic myelogenous leukaemia cells to the first-line drug imatinib Landberg et al. In AML, etomoxir sensitises cells to apoptosis-inducing treatments Samudio et al.

Another CPT1 inhibitor, ST, was shown to inhibit proliferation, survival and chemoresistance in leukaemia cell lines and primary cells by driving cells to apoptosis and causing toxic accumulation of cytosolic palmitate Ricciardi et al. Collectively, these studies indicate that inhibition or reversal of increased FA oxidation has been shown to be a suitable therapeutic intervention, in particular when combined with other cytotoxic drugs. FA metabolism is up-regulated in many cancer types, such as colorectal Zhou et al.

Metabolic adaptations of leukaemia cells to the microenvironment contribute to proliferation and disease progression Samudio et al. Cancer cells develop resistance in part by increasing FA oxidation and thus, not surprisingly, obesity is emerging as a major risk factor. This provides rational for supportive therapeutic measures through nutritional intervention. At present, it is not clear to which extent metabolic adaptations of cancer cells are either stable or transient.

Future investigations will need to explore how epigenetic mechanisms regulate and sustain metabolic states in healthy cells and also how cancers cells adapt to their microenvironment. Promising initial studies that have investigated the dependence of cancer cells on FA oxidation warrant follow-up in pre-clinical models, in particular as part of combinatorial therapies. MM and JD wrote the main body of the text.

MM and RC designed and illustrated the figures. MM, JD, and MB participated in redrafting of the manuscript and contributed feedback to the final manuscript. All authors have approved the manuscript for submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aagaard, M. Molecular basis for gene-specific transactivation by nuclear receptors. Acta , — Abdel-aleem, S. Regulation of glucose utilization during the inhibition of fatty acid oxidation in rat myocytes. Abu-Elheiga, L. Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms.

PubMed Abstract Google Scholar. Bastie, C. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CDdependent and-independent mechanisms. Beckmann, B.