A Model Cell Line to Study Regulation of Stearoyl-CoA Desaturase Gene 1 Expression by Insulin and Polyunsaturated Fatty Acids

Ntambi, James M.; Sessler, Anna M.; Takova, Tsetska

doi:10.1006/bbrc.1996.0520

Cited by 55 publications

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“…In contrast, the proportional amounts of long polyunsaturated fatty acids in the liver were strongly inversely related to hepatic SCD1 activity index and liver fat content. This is consistent with the ability of polyunsaturated fatty acids to suppress expression of both sterol regulatory element-binding protein 1c (51,52) and SCD1 (53) and activate genes involved in hepatic fatty acid oxidation (31). Subjects with NAFLD have been shown to consume less polyunsaturated fat than normal control subjects in some (54,55) but not all (56) cross-sectional studies.…”

Section: Discussionsupporting

confidence: 68%

Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

et al. 2009

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OBJECTIVE-To determine whether 1) hepatic ceramide and diacylglycerol concentrations, 2) SCD1 activity, and 3) hepatic lipogenic index are increased in the human nonalcoholic fatty liver.RESEARCH DESIGN AND METHODS-We studied 16 subjects with (n ϭ 8) and without (n ϭ 8) histologically determined nonalcoholic fatty liver (NAFL ϩ and NAFL Ϫ ) matched for age, sex, and BMI. Hepatic concentrations of lipids and fatty acids were quantitated using ultra-performance liquid chromatography coupled to mass spectrometry and gas chromatography. RESULTS-The absolute (nmol/mg) hepatic concentrations of diacylglycerols but not ceramides were increased in the NAFL ϩ group compared with the NAFL Ϫ group. The livers of the NAFL ϩ group contained proportionally less long-chain polyunsaturated fatty acids as compared with the NAFL Ϫ group. Liver fat percent was positively related to hepatic stearoyl-CoA desaturase 1 (SCD1) activity index (r ϭ 0.70, P ϭ 0.003) and the hepatic lipogenic index (r ϭ 0.54, P ϭ 0.030). Hepatic SCD1 activity index was positively related to the concentrations of diacylglycerols (r ϭ 0.71, P ϭ 0.002) but not ceramides (r ϭ 0.07, NS).CONCLUSIONS-We conclude that diacylglycerols but not ceramides are increased in NAFL. The human fatty liver is also characterized by depletion of long polyunsaturated fatty acids in the liver and increases in hepatic SCD1 and lipogenic activities. Diabetes 58: [203][204][205][206][207][208] 2009 N onalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver (Ն10% of liver weight), which cannot be attributed to alcohol consumption or any other liver disease (1). NAFLD covers a range from simple nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and fibrosis (1). The fatty liver is resistant to the action of insulin to inhibit hepatic glucose (2,3) and VLDL (4) production, resulting in hyperglycemia and hypertriglyceridemia. The mechanisms underlying insulin resistance in human NAFLD are unclear. While triacylglycerols themselves are inert, lipid intermediates may act as important regulators of both oxidative stress (5) and insulin signaling (6). In vitro studies as well as studies in animals suggest that diacylglycerols, which are immediate precursors of triacylglycerols (7), can induce insulin resistance by activating specific isoforms of protein kinase C (PKC) (8,9). The concentrations of diacylglycerols have recently been shown to be increased in human NAFLD compared with subjects with normal liver histology (10). Ceramides are another class of reactive lipids that mediate saturated fat-induced insulin resistance (6). There are no data comparing ceramide and diacylglycerol concentrations in the human liver or relating them to hepatic fat content.Sources of hepatic lipids include dietary chylomicron remnants, free fatty acids released from either adipose tissue triacylglycerols or chylomicrons hydrolyzed at a rate in excess of what can be taken up by tissues (spillover), and de novo lipogenesis (11). Increased lipolysis is a...

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Section: Discussionsupporting

confidence: 68%

Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

et al. 2009

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“…This is also reflected by the lack of response in Sertoli cells to arachidonate (Fig. 1), which has been shown by others to downregulate desaturase mRNA levels in liver cells (Ntambi et al 1996, Nara et al 2002, Tang et al 2003. Thus, the difference between liver and testis persists, also at the cellular level.…”

Section: Discussionmentioning

confidence: 70%

“…1). A decrease in desaturase mRNA levels has been observed when stimulating liver cells with dietary PUFAs, e.g., 20:4n-6 (Ntambi et al 1996, Nara et al 2002, Tang et al 2003. However, as seen in Fig.…”

Section: Essential Fatty Acid Deficiency Does Not Induce Desaturases mentioning

confidence: 99%

Essential fatty acid deficiency induces fatty acid desaturase expression in rat epididymis, but not in testis

Sæther¹,

Tran²,

Rootwelt³

et al. 2007

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On the molecular level, essential fatty acid deficiency (EFAD) has been associated with induced fatty acid (FA) desaturase expression and activity in several tissues. However, there seem to be exceptions. In the present study, we examine the effects of EFAD in the male rat genital tract, combining FA analysis, gene expression studies, and morphological evaluation of epididymal spermatozoa. When feeding 21-day-old Wistar rats, a fat-free diet for 6 weeks, an increase in 18:1n-9 and 20:3n-9 and a concomitant decrease in the 18:2n-6 and 20:4n-6 species are seen in testis, as well as in liver. However, with regard to desaturase expression the rat testis seems to be unresponsive to EFAD conditions, in contrast to other organs studied. In the sexually mature testis none of the desaturases (SCD1, SCD2, D5D, or D6D) are induced in response to lowered contents of polyunsaturated FAs. This also applies to caput epididymis, while EFAD sensitivity is regained in cauda epididymis, where the desaturases are upregulated. The FA profile of epididymal spermatozoa is increasingly affected by EFAD during the transport from testis to cauda epididymis. Furthermore, a significant increase in the number of abnormal spermatozoa is observed in cauda epididymis.

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“…The mouse isoforms share a high degree of amino acid homology (Ͼ70%), but among them, the mouse SCD1 is the best understood. It is comprised of 355 amino acids and is highly regulated by dietary and hormonal factors, including glucose (16), fructose (17), cholesterol (18), polyunsaturated fatty acids (19,20), insulin (17,21), and leptin (22). Research in recent years has unveiled the significant role of SCD1 in lipid metabolism.…”

Section: Stearoyl-coa Desaturase (Scd)mentioning

confidence: 99%

Membrane Topology of Mouse Stearoyl-CoA Desaturase 1

Man¹,

Miyazaki²,

Chu³

et al. 2006

Journal of Biological Chemistry

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Stearoyl-CoA desaturase (SCD) is an integral membrane protein anchored in the endoplasmic reticulum. It catalyzes the biosynthesis of monounsaturated fatty acids that are required for the synthesis of triglycerides, cholesteryl esters, and phospholipids. Four mouse isoforms of SCD (SCD1-4) and two human isoforms have been characterized. In the current study, we characterize the topology of the mouse SCD1 isoform. Hydropathy analysis of the 355-amino acid mouse SCD1 protein predicts that the protein contains four transmembrane domains (TMDs) and three loops connecting the membrane-spanning domains. To define the topology of the protein, recombinant SCD1 constructs containing epitope tags were transiently expressed in HeLa cells and analyzed by indirect immunofluorescence and cysteine derivatization. Our data provide evidence that the N and C termini of SCD1 are oriented toward the cytosol with four transmembrane domains separated by two very short hydrophilic loops in the ER lumen and one large hydrophilic loop in the cytosol. In addition, based on the previous observation that SCD is a thiol enzyme, we sought to investigate whether the cysteine residues were essential for enzyme activity through mutagenesis studies, and our data suggest that the cysteines in SCD are not catalytically essential. Stearoyl-CoA desaturase (SCD)2 is the rate-limiting enzyme responsible for de novo synthesis of monounsaturated fatty acids from saturated fatty acids (1-4). It is an iron-containing enzyme that catalyzes the insertion of the cis double bond at the ⌬9 position of fatty acyl-CoAs in conjunction with cytochrome b 5 reductase, cytochrome b 5 , and the cofactor NADH (5-7). The preferred substrates of SCD are palmitoyl (C16:0)-CoA and stearoyl (C18:0)-CoA, which are converted into palmitoleoyl (C16:1)-CoA and oleoyl (C18:1)-CoA, respectively (8).A number of mammalian SCD genes have been cloned and studied. Two SCD genes have been cloned in rats (9) and four (SCD1-4) in mice (10 -13). In human, two SCD genes (hSCD1 and hSCD5) have been characterized (14, 15). The mouse isoforms share a high degree of amino acid homology (Ͼ70%), but among them, the mouse SCD1 is the best understood. It is comprised of 355 amino acids and is highly regulated by dietary and hormonal factors, including glucose (16), fructose (17), cholesterol (18), polyunsaturated fatty acids (19,20), insulin (17, 21), and leptin (22). Research in recent years has unveiled the significant role of SCD1 in lipid metabolism. The products of SCD, palmitoleic and oleic acids, are the most abundant fatty acids found in triglycerides and cholesteryl esters. Significant reduction in tissue triglycerides and cholesteryl esters has been observed in a laboratory mouse model with targeted disruption in the SCD1 gene (SCD1Ϫ/Ϫ) (23). It was also found that the SCD1Ϫ/Ϫ mice have very low levels of triglycerides in the very low density lipoprotein fraction compared with the wild-type counterparts (23). More interestingly, SCD1 is the major target gene for leptin, and SCD1 deficien...

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A Model Cell Line to Study Regulation of Stearoyl-CoA Desaturase Gene 1 Expression by Insulin and Polyunsaturated Fatty Acids

Cited by 55 publications

References 0 publications

Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

Essential fatty acid deficiency induces fatty acid desaturase expression in rat epididymis, but not in testis

Membrane Topology of Mouse Stearoyl-CoA Desaturase 1

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