Role of stearoyl-coenzyme A desaturase in lipid metabolism

Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 113–121

Role of stearoyl-coenzyme A desaturase in lipid metabolism Makoto Miyazakia, James M. Ntambia,b,* b

a Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, WI 53706, USA Department of Nutritional Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA

Abstract Stearoyl-CoA desaturase (SCD) (EC 1.14.99.5) is an endoplasmic reticulum-bound enzyme that catalyzes the D9-cis desaturation of saturated fatty acyl-CoAs, the preferred substrates being palmitoyl- and stearoyl-CoA, which are converted to palmitoleoyl- and oleoyl-CoA, respectively. These monounsaturated fatty acids are used as substrates for the synthesis of triglycerides, wax esters, cholesteryl esters and membrane phospholipids. The saturated to monounsaturated fatty acid ratio affects membrane phospholipid composition and alteration in this ratio has been implicated in a variety of disease states including cardiovascular disease, obesity, diabetes, neurological disease, skin disorders and cancer. Thus, the expression of SCD is of physiological importance in normal and disease states. Several mammalian SCD genes have been cloned. A single human, three mouse and two rat are the best characterized SCD genes. The physiological role of each SCD isoform and the reason for having three or more SCD gene isoforms in the rodent genome are currently unknown. A clue as to the physiological role of the SCD, at least SCD1 gene and its endogenous products came from recent studies of asebia mouse strains that have a natural mutation in the SCD1 gene and a mouse model with a targeted disruption of the SCD1 gene. In this review we discuss our current understanding of the physiological role of SCD in lipid synthesis and metabolism. r 2002 Elsevier Science Ltd. All rights reserved.

1. Introduction A critical committed step in the biosynthesis of monounsaturated fatty acids (MUFAs) is the introduction of the cis-configuration double bond into acyl-CoAs (between carbons 9 and 10). This oxidative reaction is catalyzed by the iron-containing, microsomal enzyme, stearoyl-CoA desaturase (SCD). NADH supplies the reducing equivalents for the reaction, the flavoprotein is cytochrome b5-reductase and the electron carrier is the heme protein cytochrome b5 [1]. Based on recent kinetic isotope data [2,3], the current hypothesis for the desaturation reaction is that the enzyme removes the hydrogen atoms starting with the one at the C-9 position, followed by the removal of the second hydrogen atom from the C-10 position. This stepwise mechanism is highly specific in the position at which the double bond is introduced (between carbons 9 and 10) and implies that the C-9 and C-10 bond is accurately positioned with respect to the diiron center [4]. The desaturation of the fatty *Corresponding author. Tel.: +1-608-265-3700; fax: +1-608-2653272. E-mail address: [email protected] (J.M. Ntambi).

acid is an oxidation reaction and requires molecular oxygen and two electrons. However, oxygen itself is not incorporated into the fatty acid chain but is released in the form of water [5]. Although the insertion of a double bond occurs in a spectrum of methyleneinterrupted fatty acyl-CoA substrates including many positional and geometric isomers of monoenoic fatty acids [6], the preferred substrates are palmitoyl- and stearoyl-CoA, which get converted into palmitoleoyland oleoyl-CoA, respectively [7–9]. These MUFAs are then used as major substrates for the synthesis of various kinds of lipids including phospholipids, triglycerides (TG), cholesteryl esters (CE) and wax esters. Oleic acid is the preferred substrate for acyl-CoA cholesterol acyltransferase (ACAT) and diacylglycerol acyltransferase (DGAT), the enzymes responsible for CE and TG synthesis, respectively [10–12]. In addition oleate is the major monounsaturated fatty acid in human adipose tissue [13] and in the phospholipid of the red-blood-cell membrane [14]. The ratio of stearic acid to oleic acid has been implicated in the regulation of cell growth and differentiation through effects on membrane fluidity and signal transduction [1]. MUFAs also influence apoptosis [15] and may have some role in mutagenesis

0952-3278/03/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 9 5 2 - 3 2 7 8 ( 0 2 ) 0 0 2 6 1 - 2

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in some tumors [16,17]. Overall, SCD expression affects the fatty acid composition of membrane phospholipids, TGs and CE, resulting in changing membrane fluidity, lipid metabolism and obesity. Thus, the regulation of SCD is of considerable physiological importance and high SCD activity has been found in a wide range of diseases including diabetes [18–22], atherosclerosis [23,24], obesity [19,22,25–27] and cancer [28,29]. In this review the regulation of the SCD genes will be discussed briefly because this topic has been reviewed extensively [1,29–31]. We will focus mainly on recent studies of the physiological roles of the SCD isoforms in lipid synthesis and metabolism. These studies have advanced in the last few years due to the availability of the mouse model with a natural mutation in the SCD1 gene [32] and the mouse with a targeted disruption in the SCD1 gene that was recently generated in our laboratory [33].

2. Regulation of SCD genes The genes for SCD have been cloned from different mammalian species including, hamster [34], ovine [35,36], rat [37], mouse [38–40] and human [41]. In the mouse, three isoforms of the SCD gene have been identified, namely scd1 [39], scd2 [38] and scd3 [40], whereas in the rat two isoforms have been characterized. In many different mouse strains, all of SCD genes are localized in close proximity on chromosome 19 [40,42] and code for a transcript of about 4.9 kb [38–40]. In humans, only a single functional SCD gene on chromosome 10 has so far been characterized [41]. The second SCD locus on chromosome 17 is a fully processed pseudogene [41]. Although the mouse isoforms share 85% to 88% identity at their amino acid sequence, their 50 -flanking regions differ somewhat resulting in divergent tissuespecific gene expression [8,40]. Under normal dietary conditions, SCD1 mRNA is expressed in liver and adipose tissue and is dramatically induced in both tissues in response to feeding a high-carbohydrate diet [39]. SCD2 is predominantly expressed in brain and is developmentally induced during neonatal myelinating period [38,43]. Similar to SCD1, SCD2 mRNA is expressed to a lesser extent in kidney, spleen, heart and lung where it is induced in response to a highcarbohydrate diet [38]. In addition, SCD2 mRNA is expressed in B cells and is down regulated during lymphocyte development [44,45]. In some tissues such as the adipose and eyelid, both SCD1 and SCD2 genes are expressed [33], whereas in the skin, Harderian and preputial glands all the three gene isoforms are expressed [8,40,113]. In mouse skin, SCD1 expression is restricted to the undifferentiated sebocytes, while

SCD3 is expressed mainly in the differentiated sebocytes [32,40]. SCD2 is expressed in hair follicles [32]. Expression of the human SCD gene gives rise to two mRNA transcripts of 3.9 and 5.2 kb as a consequence of the two polyadenlyation signals indicating that the two differently expressed transcripts encode the same SCD polypeptide [41]. The function of the polyadenylation is not known but could be in addition to the transcriptional control, a means by which the two transcripts differ in stability or translatability thus allowing for rapid and efficient changes in cellular environment [41]. Many developmental, dietary, hormonal and environmental factors regulate SCD expression. High-carbohydrate fat-free diets, induce hepatic SCD1 mRNA expression [21,39,46]. Insulin [21,47,48], glucose and fructose [21,49], cholesterol [50,51], cold temperatures [52–55], light [56] and some drugs (fibrates, peroxisome proliferators) [57–59], retonoic acid [51,60,61] induce SCD gene expression in different organisms. On the other hand, polyunsaturated fatty acids (PUFA). especially of the n-6 and n-3 families [20,46,62], conjugated linoleic acid (CLA) [63,64], ethanol [65,66], tumor necrosis factor-alpha (TNFa) [67], interleukin-11 (IL–11) [68], thyroid hormone [69], cAMP (or drugs that increase its intracellular levels) [39,70] inhibit SCD1 mRNA transcription and SCD activity in the liver. Previous studies in 3T3-L1 adipocytes have shown that thiazolidinediones [71,72] and some steroid hormones reduce SCD1 mRNA levels together with reduced SCD activity [73]. Sulfur-substituted (thia) fatty acids [74,75] inhibit SCD either at the gene expression or at the enzyme activity level, while cyclopropene fatty acids (sterculic acid) directly inhibit SCD activity in vivo and in vitro [16, 76–78]. Insulin and high-carbohydrate diets induce SCD gene expression through the sterol regulatory element binding protein (SREBP-1) dependent mechanism [79,80]. Three major SREBP isoforms, SREBP-1a, SREBP-1c, and SREBP-2, are encoded by two different genes and are well characterized [80]. These proteins are synthesized as precursors and inserted into the endoplasmic reticulum (ER) membrane where they are anchored through a two-pass membrane spanning domain with both the amino and carboxylic acid domains facing the cytosolic side of the membrane. In sterol deficient cells, proteolytic cleavage of the SREBPs by the SREBP specific proteases (S1P and S2P) occurs in the golgi and releases their N-terminal mature and active forms from the membrane. This enables them to enter the nucleus, where they bind to the sterol regulatory elements (SREs) and/or E-box sequences and activate genes involved in cholesterol, TG and fatty acid biosynthesis. PUFA repress human and mouse SCD gene expression as well as other lipogenic genes by reducing the gene expression and maturation of SREBP-1 [1,31,81]. However, repression of SCD gene expression by PUFAs

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via an SREBP-independent mechanism has been suggested [82]. Cholesterol on the other hand, induces SCD by both an SREBP-1c and an LXRa-dependent mechanism [51,83]. Peroxisome proliferators induce SCD1 through PPARa [57,84], while the thyroid hormone and retinoic acid use thyroid hormone receptor [69] and RXRa [60], respectively. The mechanisms by which cyclic AMP, alcohol, temperature, CLA, IL–11, TNFa and ethanol regulate SCD have not been elucidated.

3. Role of SCD in lipid synthesis and metabolism 3.1. SCD1 in TG, VLDL, and CE synthesis More than 200 papers on SCD studies were published in the last two decades. However, we still poorly understand the physiological role of SCD and its products, the monounsaturated fatty acids. Oleate is one of the most abundant fatty acid in dietary fat and therefore readily available. Why then is SCD1 a highly regulated enzyme? The clue as to what the physiological role of the SCD1 gene and its endogenous products has come from recent studies of the asebia mouse strains (abj and ab2j) that have a naturally occurring mutation in the SCD1 gene [32,85] as well as a laboratory mouse model with a targeted disruption (SCD1/) [33]. Using these models we have shown that SCD1/ mice are deficient in hepatic TGs, cholesterol esters, wax esters and 1-alkyl-2,3-diacylglycerol [8,33,85,86]. The levels of palmtoleate (C16:1) and oleate (C18:1) are reduced while palmitate and stearate are increased in the tissue lipid fractions of SCD1/ mice [8,33,85]. Normally a high-carbohydrate diet fed to mice or rats induces SCD1 gene and other lipogenic genes resulting in increased MUFAs and hepatic TGs [46]. One of the surprises of our recent studies [86] is that on a high-carbohydrate low-fat diet the SCD1/ mice fail to accumulate hepatic TGs. In addition, upon supplementation of this diet with high levels of triolein, the CE levels are normalized but the TG levels are not reversed to the levels found in the wild-type mouse [86]. These observations reveal that endogenously synthesized MUFAs by SCD most likely serve as the main substrates for the synthesis of hepatic TGs. Because the enzymes involved in the de novo synthesis of TGs and cholesterol ester namely, ACAT and DGAT are located in the ER membrane, a possible physiological explanation for the requirement of SCD expression is for the production of more easy accessible MUFAs within the vicinity of these enzymes. Another possibility is that the MUFAs are incorporated into the TGs but the TGs are immediately hydrolyzed and the fatty acids oxidized. An experiment using [3H]-glycerol showed very low rate of TG synthesis in liver

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of SCD1/ mice [86]. Furthermore, the rate of VLDL-TG secretion, as measure by inhibition of VLDL clearance using Triton, was dramatically reduced in the SCD1/ mice [87]. Hypertriglyceridemia (HTG) syndromes are among the most common lipid disorders in humans. Although there is strong evidence that many of these syndromes are heritable [88–90], the genetics of these disorders is not well understood. It is most likely that HTG is a complex trait, i.e. multiple genes influence the expression of the phenotype. In addition, the penetrance of HTG is affected by diet, insulin sensitivity, and obesity [91]. Given the strong correlation between the ability of cells to synthesize TGs and CEs and the activity of SCD observed in mouse liver, Attie et al. [92] validated and applied a simple plasma marker of SCD activity, the ratio of plasma oleate to stearate (18:1/18:0 ratio, the ‘‘desaturation index’’), to test the hypothesis that in vivo SCD activity accounts for a large fraction of the variation in plasma TGs in human subjects. In addition the desaturation index in human subjects exposed to a regimen known to raise serum TG levels, high-carbohydrate diets was studied. The results supported an important role of SCD in human serum TG levels [92]. Cohen et al. [87] have shown that the SCD1 deficiency attenuates TG synthesis and VLDL secretion in the ob/ ob mouse. Thus, the mouse and human studies imply that SCD represents a crucial bottleneck in TG, CE synthesis and VLDL secretion. These studies have broad implication for the potential use of SCD as a target in the treatment of human HTG. The role of SCD in TG, CE synthesis, VLDL synthesis and secretion in mouse liver is depicted in Fig. 1. 3.2. Role of SCD1 in synthesis of wax esters and 1-alkyl2,3-diacylglycerol The mice with a targeted disruption of the SCD1 gene as well as the asebia mutant mice are beginning to reveal other interesting phenotypes. These mice show cutaneous abnormalities with atrophic sebaceous glands and narrow eye fissure with atrophic meibomian glands suggesting an important role for monounsaturated fatty acids in skin homeostasis [32,33,93]. It is known that the major function of sebaceous glands and meibomian gland is to secrete a lipid complex; lubricants, called sebum and mebum, respectively, containing wax ester, TG and CE [94–107]. These fluids prevent the evaporation of moisture from skin and eyeballs [108]. Blepharitis and dry eye syndrome, which are one of the most common frustrating eye disease conditions in humans, are very similar to the phenotype observed in the eye of SCD1/ mice [102–103]. It has been found that mebum from patients with meibomian keratoconjunctivitis have decreased levels of oleic acid, a major product of SCD, whereas that from patients with meibomian

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Hepatocyte Cholesterol ACAT

16:0-CoA 18:0-CoA

16:1-CoA 18:1-CoA

SCD

Cholesteryl ester

Glycerol-3-phosphate

DGAT

Triglycerides

VLDL

Fig. 1. Role of SCD in TG, CE and VLDL synthesis and secretion. SCD, stearoyl-CoA desaturase; DGAT, diacyl glycerol acyltransferase; ACAT, acyl-CoA cholesterol acyltransferase; VLDL, very-low-density lipoprotein.

seborrhea have increased levels of oleic acid [101]. Therefore, SCD expression can be implicated in some eye disorders. The skin and eyelid of SCD1/ mice are deficient in TG, CE and wax esters [33]. The levels of cholesterol are increased [33]. The benefit of expressing SCD1 would be to provide oleoyl-CoA, the preferred substrate for ACAT-mediated cholesterol esterification as a means of protecting the cell from the harmful effects of cholesterol. In addition, the presence of normal levels of MUFAs would maintain a more appropriate ratio of cholesterol to other lipids to maintain cell membrane integrity, although this concept has not been rigorously tested. The studies of SCD gene expression in the mouse Harderian gland revealed the role of SCD in the biosynthesis of another class of lipid the alky-2,3diacylglycerol (ADG) [8]. The Harderian gland that was first described by Johann J Harder at the end of the XVII century is located within the orbit of the eye where in most species it is the largest tissue [109]. The major products from this gland vary between the different species of mammals. In rodents, the gland synthesizes lipids, indoles, and porphyrins, which are secreted by exocytotic mechanism [110]. The major lipid synthesized by the mouse Harderian gland is ADG [111] and is secreted as a lubricant of the eyeball to assist in the movement of the eyelid [33,112]. In our recent study, SCD1/ mice exhibited a deficiency in ADG and the n-9 eicosenoate [20:1n-9]., which is the main monounsaturated fatty acid of ADG. We found that 20:1n-9 is an elongation product of 18:1n-9. Feeding diets containing high levels oleate or eicosenoate failed to restore the deficiency in ADG. Therefore, endogenously synthesized oleate by SCD1 as was demonstrated in liver is essential for the biosynthesis of ADG and eicosenate in the mouse Harderian gland [8].

3.3. SCD1 knockout studies reveal substrate specificity of the SCD isoforms The Harderian gland expresses the three SCD isoforms [8]. Microsomes isolated from the Harderian gland of SCD1/ mice still showed high desaturase activity toward palmitoyl-CoA, whereas the SCD activity toward stearoyl-CoA was reduced by more than 90%. These studies suggested that stearoyl-CoA was the main substrate of SCD1 isoform. The preputial gland of the mouse like the skin and Harderian gland also expresses the three SCD isoforms [113]. Interestingly, the preputial gland of SCD1/ mice lacked SCD3 expression while the expression of the SCD2 was not altered. When the SCD activity was measured in this gland it was shown that the desaturase activity towards palmitoyl-CoA was extremely low compared to stearoyl-CoA. However, treatment of the SCD1/ mice with testosterone induced SCD3 expression and lead to an increase in desaturase activity toward palmitoyl-CoA. Consistent with these observations, the levels of C16:1n-7 derived from desaturation of palmitoyl-CoA were decreased by greater than 70% in the SCD1/ mice compared to a decreased of 30% in the levels of C18:1n-9 derived from the desaturation of C18:0. Therefore, these studies strongly suggested that palmitoyl-CoA is main substrate for SCD3 isoform. The SCD1 and SCD2 preferentially utilized stearoyl-CoA as substrate of desaturation [113]. The different substrate specificity may explain why there are several SCD isoforms in the mouse genome. The differences in the catalytic selectivity of the SCD isoforms may be to contribute to the establishing of the lipid composition of the cell. A finer control can be provided by regulated expression of several isoforms with differing selectivity than by expression of either one or two with the same substrate selectivity. However, the

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physiological roles of the n-9 and n-7 MUFAs have not yet been established.

3.4. SCD1 in regulation of lipogenesis and fatty acid oxidation We recently showed that mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased insulin sensitivity and are resistant to diet-induced weight gain [111]. The protection from obesity involves increased energy expenditure and increased oxygen consumption. Compared to the wildtype mice the SCD1/ mice had increased levels of plasma ketone bodies but reduced levels of plasma insulin and leptin. DNA micro arrays were employed to identify genes whose expression was altered in the liver of SCD1/ mice. Two hundred mRNAs that were significantly different between the livers of SCD1/ and SCD1 +/+ mice were identified. The most striking pattern was genes involved in lipogenesis and fatty acid b-oxidation. Lipid oxidation genes and targets of PPARa such as acyl-CoA oxidase (ACO), very long chain acyl-CoA dehydrogenase (VLCAD) and carnitine palmitoyltransferase-1 (CPT–1), fasting-induced adipocyte factor (FIAF) were up regulated while lipid synthesis genes such as SREBP-1, FAS and mitochondrial glycerol phosphate acyl-CoA transferase (GPAT) were down regulated in the SCD1/ mice. SREBP-1c is the main SREBP-1 isoform expressed in liver and regulates the expression of lipogenic genes [114,115]. Insulin levels, dietary carbohydrate, fatty acids and cholesterol regulate the SREBP-1 gene expression and protein maturation [116,117]. Thus, the down regulation of SREBP-1 gene expression in the SCD1/ could have numerous effects on various metabolic pathways regulated by SREBP-1. For instance the induction of SREBP-1 by insulin greatly enhances the synthesis and secretion of TGs by the liver [118], but in the SCD1knockout mice, carbohydrate feeding fails to induce TG synthesis and secretion by the liver [85,86]. CPT-1, ACO, VLCAD and FIAF are known targets of PPARa [84,119,120]. and contain PPARa response regions in their promoters [119,121,122]. Since PPARa mRNA is unchanged (unpublished), the up regulation of enzymes of fatty acid b-oxidation in the SCD1/ mice must be downstream of PPARa gene transcription. Thus, the characteristics exhibited by the SCD1/ mice are consistent with presence of a PPARa activator with reduced activity in wild-type mice. The SCD1/ mice exhibit increase in the contents of saturated fatty acids (C16:0 and C18:0) while the contents of the PUFAs of the n-6 and n-3 are not changed [33,85,86]. One possible mechanism is that the saturated fatty acids induce the signal in the SCD1/ mice that activates the PPARa but this has yet to be determined.

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Cohen et al. [87] have recently shown that SCD1 gene is a target of leptin signaling. Leptin represses the expression of the SCD1 gene and the SCD1 deficiency normalizes the hypo-metabolic phenotype of the ob/ob mice suggesting that leptin-specific down regulation of SCD1 is an important component of the novel metabolic response to this hormone. The repression of the SCD1 gene expression by leptin resulted in increased levels of C18:0- or C16:0CoAs providing another possible mechanism of increased fatty acid oxidation in the SCD1/ mice. The saturated fatty acyl-CoAs, but not monunsaturated fatty acyl-CoAs, are known to allosterically inhibit acetyl CoA carboxylase-1(ACC), thus reducing cellular levels of malonyl CoA [87]. Malonyl-CoA is required for fatty acid biosynthesis and also inhibits the mitochondrial (carnitine palmitoyl transferase shuttle system, the rate-limiting step in the import and oxidation of fatty acids in mitochondria. Thus, reduced levels of SCD1 would lead to a decrease in the cellular levels of malonyl-CoA and resulting in increased transport of fatty acids into the mitochondria for oxidation.

4. Conclusion In conclusion, the recent studies using the knockout mouse models have revealed the phenotypes generated as a result of SCD1 gene deficiency. We have learnt that this enzyme is critical in the biosynthesis of neutral lipids; TGs, cholesterol esters, wax esters and 1-alkyl-2,3-diacylglycerol. The SCD isoforms seem to have different substrate specificity providing an explanation for the existence of several SCD isoforms in the mouse genome. We have also learnt that SCD1 deficiency either directly or indirectly induces a signal that activates the PPARa pathway to partition fat towards oxidation and down regulates SREBP-1 expression thereby reducing lipid synthesis and storage. In addition, the SCD1 deficiency leads to resistance to diet-induced obesity, increased insulin sensitivity and increased metabolic rate. SCD1 is also a target of leptin signaling. Thus, in addition to playing a role in lipid metabolism the SCD1 is a promising therapeutic target. It will be interesting to generate mouse knockouts of the other SCD1 isoforms and determine their phenotypes.

Acknowledgements We thank Brian Fox, Alan Attie and Jeffrey Friedman for useful discussions We thank Enrique Gomez for his critical comments during the preparation of this review.

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