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15[1] REVIEW Stearoyl CoA Desaturase 1: Role in Cellular Inflammation and Stress1,2 Xueqing Liu,3 Maggie S. Strable,4 and James M. Ntambi3,4٭ 3Department of Biochemistry and 4Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706 ABSTRACT ...

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REVIEW Stearoyl CoA Desaturase 1: Role in Cellular Inflammation and Stress1,2 Xueqing Liu,3 Maggie S. Strable,4 and James M. Ntambi3,4٭ 3Department of Biochemistry and 4Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706 ABSTRACT Stearoyl CoA desaturase 1 (SCD1) catalyzes the rate-limiting step in the production of MUFA that are major components of tissue lipids. Alteration in SCD1 expression changes the fatty acid profile of these lipids and produces diverse effects on cellular function. High SCD1 expression is correlated with metabolic diseases such as obesity and insulin resistance, whereas low levels are protective against these metabolic disturbances. However, SCD1 is also involved in the regulation of inflammation and stress in distinct cell types, including b-cells, adipocytes, macrophages, endothelial cells, and myocytes. Furthermore, complete loss of SCD1 expression has been implicated in liver dysfunction and several inflammatory diseases such as dermatitis, atherosclerosis, and intestinal colitis. Thus, normal cellular function requires the expression of SCD1 to be tightly controlled. This review summarizes the current understanding of the role of SCD1 in modulating inflammation and stress. Adv. Nutr. 2: 15–22, 2011. Introduction Great diversity exists in the structures and functions of the vast ar- ray of lipid species. Lipids are essential for a number of processes that support cellular and tissue maintenance such as the synthesis of cellular membranes, signal transduction, energy storage, assem- bly of lipoprotein particles, protein modification, as well as many other important functions. Intracellular levels of lipids are tightly regulated by a network of metabolic pathways to sustain normal cellular functions. The regulated synthesis of major lipid classes, in- cluding phospholipids, TG, cholesterol esters (CE),5 and wax esters (WE), incorporates fatty acids, of which MUFA are preferred sub- strates (1,2). These different lipids possess distinct biological func- tions and therefore disturbance of the cellular MUFA profile may produce diverse metabolic and systemic effects that include inflam- mation and stress. The intracellular levels of MUFA are controlled by stearoyl-CoA desaturase (SCD), a family of enzymes that are D-9 fatty acid desa- turases. Anchored in the membrane of the endoplasmic reticulum, SCD catalyzes the biosynthesis of MUFA from dietary or de novo synthesized SFA precursors (Fig. 1). Four SCD isoforms (SCD1–4) have been identified in the mouse genome and 2 SCD isoforms (hSCD1 and 5) have been reported in humans (3–7). The SCD iso- forms exhibit different tissue distribution patterns but share the same enzymatic function. A number of articles have reviewed the SCD isoforms in detail (8,9). Of these isoforms, SCD1 is the pre- dominant one and is expressed ubiquitously among tissues, with constitutively high levels in adipose, meibomian gland, Harderian gland, and preputial glands and is highly induced in liver in response to a high-carbohydrate diet (2,10). SCD1 contains a 33- amino acid sequence at the N terminus that leads to the rapid deg- radation of this enzyme via a ubiquitin-dependent proteasome mechanism (11,12). In addition to post-translational control of SCD1 protein level, SCD1 gene expression is highly sensitive to a number of dietary, hormonal, and environmental factors. High- carbohydrate diets, glucose and fructose, cholesterol, and vitamins A and D induce SCD1 expression (13–18), whereas PUFA, espe- cially the (n-3) and (n-6) families, and conjugated linoleic acid inhibit the expression of SCD1 (13,19,20). Furthermore, transcrip- tional control of SCD1 has been shown to be mediated by several transcription factors, including liver X receptor, sterol response el- ement binding protein 1c, carbohydrate response element binding protein, PPAR, and estrogen receptor, as reviewed elsewhere (8,9). Substantial insights into the physiological functions of SCD have been gained through studying genetically engineered whole body and tissue specific SCD1 knockout models (21–23). Research using other models of SCD1 suppression has also provided impor- tant knowledge for SCD function, these models included Asebia mice that have a natural mutation in SCD1 and thus whole body deficiency of SCD1 protein, and mice treated with antisense oligo- nucleotides (ASO) against SCD1 (24,25). With increasing preva- lence of metabolic diseases such as obesity and type II diabetes, considerable research efforts have been dedicated to understanding the role of SCD in a number of metabolic diseases that are associ- ated with abnormal lipid metabolism. It is well established by past 1 Supported by NIH grant RO1-DK62388 to James Ntambi. 2 Author disclosures: X. Liu, M. S. Strable, and J. M. Ntambi, no conflicts of interest. ٭To whom correspondence should be addressed. ntambi@biochem.wisc.edu. 5 Abbreviations used: Ab, b-amyloid peptide; ASO, antisense oligonucleotide; CE, cholesterol ester; DSS, dextran sulfate sodium; HAEC, human arterial endothelial cell; HSVLF, high-sucrose very low-fat diet; MCD, methionine choline deficient diet; LDLR2/2, LDL receptor knockout; SCD, stearoyl CoA desaturase; SKO, skin specific knockout; TLR, Toll-like receptor; WE, wax ester. ã2011 American Society for Nutrition. Adv. Nutr. 2: 15–22, 2011; doi:10.3945/an.110.000125. 15 Administrator 注释 脂肪酸代谢 Administrator 注释 本文主要介绍SCD1在调节免疫和应激中的作用/角色。 Administrator 铅笔 Administrator 注释 此段介绍SCD的基本情况。 Administrator 下划线 Administrator 下划线 Administrator 注释 肝脏在高糖饮食的诱导下可高表达SCD Administrator 注释 要想研究细致必然需要研究其各种代谢反应,即;这个物质在体内是如何变化的。 Administrator 下划线 Administrator 下划线 Administrator 下划线 Administrator 注释 我们要认识两点:1SCD与腹部脂肪代谢有关,这非常重要。2无论是高血糖,高血脂,高血压,高尿酸等,全是代谢亢进的一种表现,是人体摄入过多物质后的一种正常反应,另外,肥胖也一定是代谢过旺时的能量积累和存储。热量/能量是人体维持生命活动的必需物质,就目前所知,人体的基本能量单位是ATP,也就是说所有物质一定是通过ATP来实现的,这与生活中赚钱很类似,能量分为两种形式;一种是快能量,一种是慢能量。快能量就像一碗热汤,喝进去马上热,但很快这种能量就会消失,这种能量更像是一种微波/红外线,就像人不可能通过烤手,或者取暖而长也就是说这种能量就没有能够进入人体的能量合成转运系统,因此,不能转化成自己的,只有进入人体自身能量系统,才能够合成转化成自身物质,因此,不管喝水长肉,还是多吃不长肉,其关键就在于自身合成转化系统,我想这个系统能就很可在线粒体。线粒体的调控基因属于管家基因,全身各细胞,组织,器官均有表达,且他们受到大脑,及激素的调控,负责全身供能。他就好像是人体的中央空调,或者是供热系统,也好像轮船的发动机,正是因为他的正常工作,才能保证一切活动的正常运转。因此线粒体使我们研究的重点。 Administrator 铅笔 studies that SCD1 deficiency protects against dietary (high-fat and high-carbohydrate induced) and genetic (leptin deficient and agouti induced) forms of obesity and liver steatosis (26–30). These results generated from studying mice with global deficiency of SCD1 led to the investigation of specific tissue(s) that might be re- sponsible for the observed phenotypes. The treatment of wild type C57/B6 mice with ASO against SCD1, which reduced SCD1 expres- sion in liver and adipose tissue, led to dramatic beneficial metabolic outcomes, including reduced weight gain and increased energy ex- penditure, when fed a high-fat diet compared with control mice (25). Targeted disruption of SCD1 in liver (SCD1 liver knockout) via cre-mediated elimination reduced weight gain and white adipose tissue fat mass caused by long term feeding of a high- carbohydrate diet (22). Furthermore, because SCD1 deficient mice exhibit a severe skin phenotype, including alopecia, atrophy of se- baceous glands, dermatitis, and increased permeability of the skin barrier (21,24), the development of a skin specific knockout (SKO) mouse model allowed us to probe the role of skin MUFA synthesis in whole body metabolic homeostasis. With comparable skin defects to SCD1 global knockout mice, SCD1 SKO mice were unexpectedly shown to be hypermetabolic and completely protected from high-fat diet induced obesity (23). A catabolic state induced by reduced skin SCD1 expression and MUFA content is likely to mediate the protective effects against the unfavorable phenotypes caused by the long term consumption of a high-fat diet. While normal functional cells require fatty acid metabolism for survival, cancer cells demand an even higher degree of metabolic flux to support their rapid growth, and SCD1 has been implicated in the pathology of cancer (31–33). Increased SCD expression has been detected in malignant human tissues such as colonic and esophageal carcinomas, as well as in hepatocellular adenoma (34), and elevated conversion of stearic to oleic acid has also been observed in transformed tumor cells (35). Due to the funda- mental need of lipid biosynthesis by tumor cells, suppression of SCD1 may produce extensive consequences on several phenotypic features of cancer encompassing cell replication, enhanced cell sur- vival, and increased tumor cell invasiveness (33). The impact of the inhibition of SCD1 on cancer cell growth also appeared to be uni- versal among different neoplastic cells, including lung, breast, pros- tate, and colon cancer cells (33,36–40). However, lower SCD expression was reported in a study that compared prostate carci- noma to normal prostate epithelium (41). Overall, these studies suggest that SCD activity and MUFA availability correlate with ma- lignant cell survival and proliferation. SCD1-deficient mice are characterized by a reduction in the percentage of fatty acids comprised of MUFA and an increase in the percentage of SFA. The reduction in MUFA levels significantly decreases the synthesis of neutral lipids such as TG and CE (2,21,42). Thus, the limited MUFA availability in SCD1-deficient mice may influence the partitioning of fatty acids into and out of neutral lipid species whose dysregulation might lead to a variety of cellular inflammatory and stress responses. In the pathology of obesity, chronic inflammation has been established as a causa- tive factor for the associated disorders such as insulin resistance and cardiovascular disease (43,44). Given the potent regulation of obesity by SCD1, it is conceivable that this enzyme is involved in modulating cellular inflammation and stress. FIGURE 1 Role of SCD in pathological processes. SCD1 mediates the synthesis of MUFA from dietary or endogenously synthesized SFA. Loss of SCD1 results in a favorable metabolic profile, including an increase in insulin sensitivity and a decrease in hepatic steatosis and adiposity. Inhibition of SCD1 is also associated with a reduction in cancer cell growth. Additionally, suppression of SCD1 alters cellular function by modulating inflammation and stress in a number of cell types and tissues, such as adipocytes, liver, macrophages, aorta, skin, myocyte, b-cell, and endothelial cell. The asterisk denotes mixed observation in a tissue or cell type. 16 Liu et al. Administrator 下划线 Administrator 注释 一切都是饱和脂肪酸惹的祸,SCD参与了不饱和脂肪酸转化成饱和脂肪酸的过程,而饱和脂肪酸则产生一系列的问题。 Administrator 注释 SCD表达缺陷对人体是有正面作用的, Administrator 铅笔 Administrator 注释 利用ASO抗SCD1治疗发现可取的良好效果:减轻体重,增加能量消耗。 Administrator 注释 这句话很重要,SCD的作用和多不饱和脂肪酸与大量细胞的生存、增殖都很重要。 Administrator 下划线 While studies aimed at understanding the role of SCD1 in reg- ulating metabolic homeostasis have been pursued, more recent re- search suggests that the beneficial metabolic effects due to loss of SCD1 may be accompanied by detrimental outcomes such as skin alopecia and inflammation, pancreatic b-cell dysfunction, liver dysfunction, and increased atherosclerosis under certain con- ditions. SCD1 has also been implicated in the regulation of adipo- cyte inflammation, macrophage inflammation, and myocyte and endothelial cell function. In this review, we discuss recent findings of the function of SCD1 in the modulation of cellular inflammation and stress and its role in the related disorders. Role for SCD1 in modulating cellular inflammation and stress SCD1 is a key regulatory enzyme controlling the homeostasis of MUFA and SFA, 2 major types of fatty acids in mammalian cells. Modulation of cellular inflammation by fatty acids has long been recognized. Earlier studies demonstrated that dietary (n-6) PUFA such as arachidonic acid [20:4(n6)] promotes cellular inflamma- tion after conversion to eicosanoids by cyclooxygenase enzymes (45). Whereas long-chain (n-3) PUFA such as EPA and DHA are able to incorporate into cell membrane phospholipids, they reduce the availability of arachidonic acid for the production of eicosa- noids and thus suppress inflammatory responses in immune cells (46). More recent studies identified FFA, especially SFA, as potent proinflammatory factors in a variety of cell types such as macro- phages, hepatocytes, and myocytes (47–49). SFA may directly pro- mote inflammation by serving as ligands of immune receptors at the cell surface, such as members of the Toll-like receptor (TLR) family (47,50). Subsequently, the downstream effectors, including mitogen-activated protein kinase 1 and NF-kB, initiate potent proinflammatory responses (43,51). Additionally, fatty acids can be taken up by cells and metabolized to lipid intermediates, includ- ing diacylglycerols and ceramides, which are potent proinflamma- tory factors (44,52,53). Prolonged and unresolved inflammatory response due to abnormal levels of bioactive lipids leads to the on- set of cellular stress response and dysfunction, eventually resulting in cell death and systemic degeneration in a process referred to as lipotoxicity (54). Lipotoxicity is regarded as one of the major causes for the pathology of obesity, insulin resistance, and cardiovascular disease (55,56). The pathophysiological mechanism of metabolic diseases substantially overlaps with those pathways regulating in- flammatory response (57,58). Given its prominent regulation of fatty acid profile and strong association with metabolic diseases, SCD1 also exhibits potent regulatory roles in cellular inflammation and stress responses in a variety of cell types and disease conditions. Liver dysfunction and stress Due to the central role of liver as the hub of numerous metabolic pathways, studies targeting liver SCD1 have been conducted to elu- cidate the role of hepatic SCD1 in regulating metabolism. Although loss of SCD1 expression in liver provides beneficial metabolic ef- fects such as reduced liver steatosis, several studies have found that SCD1 expression is strongly involved in the maintenance of liver function under a variety of stressful conditions. Hepatic SCD1 expression is substantially diminished in mice fed a methio- nine and choline deficient diet (MCD), a dietary model of steato- hepatitis (59,60). When SCD1 deficient mice were fed MCD, even though they had decreased liver steatosis, they exhibited increased hepatocellular stress response and liver injury compared with wild type mice through a mechanism of inefficient partitioning of SFA into MUFA for proper storage (60). Consistent with these reports, SCD1 deficient mice fed a high-sucrose very low-fat diet (HSVLF) also displayed severe liver stress response with liver injury despite reduced hepatic lipogenesis (61). This study reported that HSVLF stimulates an unfolded protein response with an acute induction of inflammation andmacrophage recruitment in the liver of SCD12/2 mice. However, another study using a concanavalin A induced hepatitis mouse model demonstrated a favorable effect of SCD1 de- ficiency on steatohepatitis by reducing leptin production (62). Un- like MCD or HSVLF dietary models in which hepatocytes might be the primary cell type affected, treatment with concanavalin A, a T-cell mitogen, acts mainly at NK T cells and induces a set of proinflammatory cytokines leading to liver injury (63,64). Thus, in addition to other variances, the different approaches inducing hepatic inflammation and injury in these studies may account for the different observations regarding the role of SCD1 in the regu- lation of hepatic function. These diverse inflammation regulatory effects of SCD1 deficiency warrant further studies to determine the role of SCD1 in liver function. b-Cell dysfunction Due to the proinflammatory activity of SFA, a potential patholog- ical outcome in response to SCD1 deficiency is the induction of in- flammatory and cellular stress responses. Indeed, using pancreatic b-cells as model systems, several studies have demonstrated that in- hibition of SCD1 promotes cellular stress and b-cell dysfunction (65–67). b-Cells are highly sensitive to SFA induced lipotoxicity (67,68). The ability to upregulate SCD1 expression in a subpopu- lation of b-cells rendered these cells resistant to SFA induced cell death, whereas inhibition of SCD1 activity increased their suscep- tibility to the detrimental effect of SFA (69). The conversion of lipotoxic SFA to MUFA by SCD1 is perhaps the mechanism respon- sible for maintenance of b-cell function (66,70). Although inhibi- tion of SCD1 was shown to be detrimental to b-cells in vitro, experiments using SCD1-deficient animal models have demon- strated metabolic beneficial effects from loss of SCD1, including improved insulin sensitivity (2,9,71). The observations from in vitro and in vivo studies regarding the function of SCD1 in diabetes appeared paradoxical. A more recent study using a ob/ob obesity mouse model uncovered an in vivo link between SCD1 and b-cell function. Even though protected from obesity, b-cells from ob/ob:SCD12/2 mice actually exhibited features of SFA induced lipotoxicity and substantial loss of insulin secretory function, thus resulting in severe diabetic condition (30,72). Comparison of phenotypes of SCD1 deficiency in diet induced obesity and Agouti induced obesity with those observed in the ob/obmodel fur- ther revealed that leptin gene expression was required for the im- proved insulin sensitivity by loss of SCD1 (30). The mechanism responsible for the leptin dependence of SCD1 deficiency in the regulation of insulin sensitivity remains to be determined. Adipocytes and adipose tissue inflammation Although SCD1 deficiency appears to be disadvantageous for b-cell function, this stress response is not universal for all cell types. Our recent study demonstrated that SCD1 deficiency protected mice from white adipose inflammation in both high-fat diet induced and Agouti induced obesity (73). Using isolated primary adipo- cytes, this study reported that SCD1 deficient adipocytes exhibited a reduced inflammatory response to treatment with LPS. They also elicited less paracrine stimulation of inflammation in macrophages and endothelial cells (73). Interestingly, the attenuated paracrine effects on inflammation due to SCD1 deficiency were attributed to the reduced levels of oleate, a major MUFA produced by SCD1. In fact, levels of SFA released by SCD1 deficient adipocytes were comparable to those released by wild type adipocytes. SCD1 modulates inflammation and stress 17 Administrator 下划线 Administrator 下划线 Administrator 注释 这才是本文重点,另外,SCD1是对减轻体重,增加能量消耗有好处,但是会造成很多别的问题, Consistently, in a separate study, oleate was also reported to pro- mote inflammation when added to macrophage cells (50). These observations highlight an underappreciated proinflammatory ac- tivity of MUFA in specific contexts. Additionally, in a recent study using tissue inhibitor of metalloproteinase 3 knockout models, the authors reported that elevated SCD1 expression was one of the markers associated with the increased white adipose tissue and liver inflammation (74). The differential cellular inflammatory response in adipocytes and b-cells with loss of SCD1 might be associated with their different abilities to metabolize SFA, for which adipo- cytes have greater capacity than b-cells. Macrophage inflammation and atherosclerosis Macrophages are another model system that has received substan- tial attention due to their inflammatory response with respect to SCD1 deficiency. In an earlier study of the effect of b-amyloid peptide (Ab) on macrophage inflammation, an oligonucleotide microarray screening identified that SCD1 was specifically and sig- nificantly upregulated by Ab in addition to a set of proinflamma- tory genes (75). Although SCD1 expression was implicated in Ab induced macrophage inflammation, no mechanism was proposed for its action. We recently demonstrated t
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