Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SCD (Stearoyl-CoA Desaturase)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101551

Synonyms

Historical Background

Stearoyl-CoA desaturase (SCD), also known as delta-9-desaturase, is a membrane-bound enzyme that together with NADH-cytochrome b5 reductase and cytochrome b5 introduces a cis double bond in palmitoyl-CoA and stearoyl-CoA between their ninth and tenth carbon atom counted from the carboxyl site (Fig. 1).
SCD (Stearoyl-CoA Desaturase), Fig. 1

Conversion of C16:0 to C16:1 n-1 and C18:0 to C18:1 n-9 by SCD1 is the result of the introduction of a double bond between carbon 9 and 10 counted from the COOH site. The oxygen (O) molecules are depicted in red, hydrogen (H) in white, and carbon in gray (C). Structures are derived using the MOLVIEW program (http://molview.org)

Reaction Equation Facilitated by SCD
$$ {\displaystyle \begin{array}{l}\mathrm{palmitoyl}-\mathrm{CoA}+2\; \mathrm{ferrocytochrome}\; \mathrm{b}5+{O}_2+2\; {H}^{+}+ SCD=>\mathrm{palmitoleoyl}-\mathrm{CoA}+2\; \mathrm{ferricytochrome}\ \mathrm{b}5\; +\; \quad {\mathrm{H}}_2O+ SCD\\ {}\mathrm{stearoyl}-\mathrm{CoA}\quad +\; 2\ \mathrm{ferrocytochrome}\ \mathrm{b}5+{\mathrm{O}}_2+2\ {\mathrm{H}}^{+}+\mathrm{SCD}=>\mathrm{oleoyl}-\mathrm{CoA}+2\ \mathrm{ferricytochrome}\ \mathrm{b}5+2\; {\mathrm{H}}_2O+ SCD\\ {}\end{array}} $$

The enzyme entry for SCD is EC 1.14.19.1, and its alternative names are fatty acid desaturase (FADS) or acyl-CoA desaturase. The enzyme was already described in rat liver microsomes and named stearoyl-CoA desaturase as of 1968 (Gurr et al. 1968). In the meantime, it is detected in plants, fungi, bacteria, nematodes, octopi, and so far in all animals and fish tested for the enzyme. In 1974, it was shown that SCD is regulated by diet; saturated fatty acids increase its activity (Mercuri et al. 1974), while desaturated fatty acids have negative effects on SCD expression (Jacobs et al. 2013). Its products, desaturated fatty acids, are used in various processes like triglyceride synthesis, membrane lipid synthesis, and cholesteryl synthesis. The gene was first partially cloned in humans in 1994 and fully sequenced in 1999, while its promotor region was unraveled in 2001 (Li et al. 1994; Zhang et al. 1999, 2001). In humans, there are two highly homolog isoforms SCD1 and SCD2 (also often called SCD5), whereas in most rodents there are four SCD isoforms. SCDs are reported to play an important role in lipid metabolism, fat storage, membrane integrity, immune system, brain function, growth, differentiation, cancer, and skin. Its main role is to maintain the proper lipid content which is monitored by lipid sensors like the peroxisome proliferator-activated receptors (PPARs) or sterol regulatory element-binding proteins (SREBPs).

Homology of SCD

All SCDs (37–45 kDa) share common domains and are highly homologous to each other that are highly conserved even over phyla (Fig. 2). When comparing the SCDs in vertebrates, the homology is minimally 99.6% similar (the maximum genetic distance observed was between Danio rerio and Mus musculus and Danio rerio and Rattus norvegicus, both 0.473) over the 18 species (including Homo sapiens) analyzed (Salmani Izadi et al. 2014). The three-dimensional structure was nicely revealed by Bai and co-workers in 2015 (Bai et al. 2015). The SCD protein contains four transmembrane domains. There are nine conserved histidine residues, eight of them belong to two HXXH and one HXXXXH motives and the ninth to a NXXXH motive (Bai et al. 2015). All histidine residues are presented at the same site of the membrane (Fig. 3). The eight histidine residues are essential for the enzyme’s function as SCDs lose its enzymatic capacity upon mutation (Shanklin et al. 1994). Furthermore, binding sites for binding the acyl-CoA to SCD1 are conserved and present inside as well as outside the transmembrane domains.
SCD (Stearoyl-CoA Desaturase), Fig. 2

Homology of SCDs: Alignment of SCDs derived from a selection of various phyla and order using MUltiple Sequence Comparison by L og- Expectation (MUSCLE) (McWilliam et al. 2013). The species name including the protein identification number (protein ID) is provided in front of the amino acid sequence. In green are depicted the transmembrane domains (TMD1–4) and in red the conserved histidines, three histidine boxes (HB1-3), and one conserved histidine (H). The place where the coenzyme A (Co) is located is colored in blue, in yellow is the binding site for the acyl (A), and the “p” is a putative site for phosphorylation

SCD (Stearoyl-CoA Desaturase), Fig. 3

SCD structure: Schematic representation of the structure of SCD based on the structure as published by Bai et al. (2015)

Regulation of SCD

The human SCD1 promotor region contains various transcription factor elements including lipid metabolism-specific elements for C/EBP, PPAR, and SREBP binding. This fits with the findings that the SCDs are regulated by diet. For instance, PPARs can bind to the PPAR-responsive elements in the SCD promotor and are thereby able to regulate SCD mRNA expression (Yao et al. 2016). Besides PPARs, SREBPs are thought to play a main role in the regulation of SCD expression under normal conditions. The unsaturated fatty acids repress the cleavage of SREBP present in the Golgi apparatus. SREBP is then unable to bind to the promotor of SCDs, and the expression of SCDs lowers (Aguilar and de Mendoza 2006; Yao et al. 2016) (Fig. 4). In addition, the AP1, cMyc, and N-Myc binding sites are present in the human SCD1 promotor. The transcription factors that bind to these elements are involved in cell cycle regulation. This supports that SCDs are regulated by cell cycle control genes and that SCDs are important for cell growth, differentiation, and aging (Ford 2010). Furthermore, transcription factors involved in inflammation like cRel and NF-κB are present in the human SCD1 promotor and likely to regulate also SCD1 mRNA (Zhang et al. 2001; Cui et al. 2015). In humans, SCD1 is highly expressed in adipose tissue and liver, while it is also detectable in other tissues where its expression level is relatively low and SCD2 is mainly expressed in the brain (Castro et al. 2011). Besides through the diet, SCDs are also regulated by temperature, at least in fish (Cossins et al. 2002). As temperature lowers, SCD is increased, and therefore, more unsaturated fatty acids are incorporated in cellular membranes. This results in maintaining membrane fluidity at lower temperatures.
SCD (Stearoyl-CoA Desaturase), Fig. 4

Regulation of SCD: Simplified model of the regulatory components of SCD mRNA transcription. The fatty acids (FA) have both stimulatory as well as inhibitory effects depending on the fatty acid composition. Unsaturated fatty acids (UFA) have an inhibitory effect on SREBP cleavage in the endoplasmatic reticulum (ER) and thereby inhibit SCD expression. The response elements present in the human SCD promotor are the activator protein 1 (AP-1), NF-κB, PPAR-responsive elements (PPRE), and a cholesterol response element

Role in Metabolic Disturbances

For a long time, SCDs are thought to play an important role in metabolism and also the metabolic syndrome (for an extended review, see Popeijus et al. 2008; Sampath and Ntambi 2011). SCD1 knockout mice are protected against obesity. Interestingly, these mice have increased fatty acid burning. This shows that the SCD1 enzyme is needed for proper fat storage and that if this is not possible, the excess of fatty acids is shuttled toward fat burning. Furthermore, injection of antisense oligos directed against SCD1 mRNA in lean mice protected them of becoming insulin resistant and caused less weight gain compared to their untreated littermates. SCD knockout also resulted in skin problems and cold sensitive mice as reviewed by Sampath and Ntambi (2014). This is in line with a study in Caenorhabditis elegans where SCDs induced cold tolerance (Savory et al. 2011). As in mice, similar results were found in rats. Rats treated with SCD1 antisense oligos were protected to develop liver insulin resistance and gained less weight on a high-fat diet compared to their controls (Gutierrez-Juarez et al. 2006). Interestingly, downregulation by either antisense oligos or lentiviral delivery of short hairpins of SCD2, which are highly expressed in the hypothalamus, resulted in increased energy expenditure (de Moura et al. 2016). This shows that SCDs play also an important role in the energy expenditure of the whole body. Taken together, these data suggest clearly that SCDs play an important role in (fat) metabolism and are associated to metabolic disturbances. However, it should be kept in mind that although it is tempting to consider SCDs as targets to treat metabolic disturbances, SCDs also have beneficial functions in maintaining the proper fatty acid balance in, for example, membranes and lipid droplets in muscle, liver, and fat cells. Moreover, SCD isoforms are clearly expressed in the brain, where they are likely involved in maintaining proper brain lipid content which is considered to be highly important for proper brain function. For example, in Alzheimer’s disease, SCD was reported to be upregulated (Astarita et al. 2011) which may be linked to dietary problems. This also suggests that controlling a proper balance of saturated and unsaturated fatty acids in the brain by SCD in combination with diet might be protective to cognitive decline such as Alzheimer’s disease (Zhang et al. 2016). This is supported by the finding that inhibition of SCD also inhibited neuron synaptic migration (Polo-Hernandez et al. 2014). Besides these beneficial effects in the brain, SCDs turned out to be protective against myocardial apoptosis following saturated fatty acid-induced stress, by shuttling the overflow of fatty acids toward storage (Matsui et al. 2012). Altogether, it remains questionable to inhibit SCD using pharmacological drugs as new treatment to counter the metabolic syndrome.

Role in Cancer

As already mentioned, SCDs seem to protect against saturated fatty acid-induced apoptosis in cardiomyocytes (Matsui et al. 2012). In addition, SCDs are upregulated in many cancer types including breast, prostate, and lung cancer (Popeijus et al. 2008; Peck et al. 2016; Peck and Schulze 2016). Peck et al. (2016) show in their review that based on data taken from various studies, on breast and prostate cancers, SCD expression is upregulated and correlates with tumor progression (Peck et al. 2016). Furthermore, silencing using antisense oligos directed against SCD mRNA reduced growth and survival under low serum conditions. This was supported by the finding that SCD inhibitors 4-(2-chlorophenoxy)-N-(3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide and 3-[4-(2-chloro-5-fluorophenoxy)-1-piperidinyl]-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyridazine both dose dependently inhibited cell growth and survival under low serum conditions. Interestingly, oleic acid was able to relieve the inhibition of the SCD inhibitor (Peck et al. 2016). They also observed that serum deprivation increased de novo FA synthesis and SCD activity. This strengthens the idea that SCD is essential for cell proliferation and vitality and therefore also for cancer cell growth. Besides breast and prostate cancer, also in lung cancer, inhibition of SCD resulted in inhibited cell proliferation and increased apoptosis (Hess et al. 2010). Hess et al. (2010) report that a 75% reduction of the cells in S-phase was observed, so actually cells were stuck at the G1/S boundary of the cell cycle and were unable to proceed in the cell cycle. Under low serum conditions also a reduction in G2/M fase was observed. Interestingly, in agreement with Peck et al. (2016), the authors also see that the addition of oleic acid is able to reverse the effects of SCD inhibition (Hess et al. 2010; Peck et al. 2016). Therefore, based on these effects of SCD inhibition on reduce cancer growth and increase cancer cell apoptosis, many drugs that inhibit SCD1 are currently under investigation (reviewed by Uto (2016)). However, it seems possible to counter the effects of SCD inhibition by exogenous fatty acid supplementation. This suggests that for cancer treatment, targeting SCDs should also include dietary modulations.

Summary

SCD are able to modulate fat storage and fatty acid compositions of cellular membranes. In the metabolic syndrome, increased levels of SCD are observed that go together with increased insulin resistance and dyslipidemia. Still, nearly all studies focus on downregulation of SCD as this was reported in to be beneficial with regard to increased insulin sensitivity and fat redistribution toward fat burning. However, the increased levels of SCD may actually be insufficient to fully counter the metabolic unbalance of the metabolic syndrome. This hypothesis is supported by a study in rats where the liver X receptor (LXR) agonist that significantly increased SCD, probably via SREBP, completely diminished high-fat-induced muscle insulin resistance (Baranowski et al. 2014). Therefore, modulation of SCD by drugs in order to treat metabolic syndrome should be carefully considered in the light of the potential beneficial effects of SCD.

For cancer, the story might be slightly different. Current data show clearly that SCDs play an important role to maintain the proper lipid content of the cells. In addition, decreased SCD levels by SCD inhibitors hinder cell cycle progression. This might be due to the inability of the cell to properly increase the amount of cellular membranes. This might also explain why downregulation of SCD inhibits cell growth and result in increased apoptosis. The cancer cells cannot stop dividing, and therefore, they are directed toward apoptosis when there is too much disturbance in membrane integrity and proper fat handling. Therefore, research to discover new SCD inhibitory components would be highly relevant as inhibition of SCD seems to be a valuable addition in cancer treatment. In addition, as these inhibitors might have negative side effects on brain and cognitive function. Therefore, the effects of SCD and its inhibitors on brain and cognitive function should be studied. Finally, as the effects of the inhibitors can be reversed through “diet,” it is worth to take into account the nutritional status during cancer treatment as well.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Human BiologyMaastricht UniversityMaastrichtThe Netherlands