Identification and Characterization of a Novel Δ6/Δ5 Fatty Acid Desaturase Inhibitor As a Potential Anti-Inflammatory Agent

Obukowicz, Mark G.; Raz, Amiram; Pyla, Paul D.; Rico, Joseph G.; Wendling, Jay M.; Needleman, Philip

doi:10.1016/s0006-2952(97)00665-5

Cited by 53 publications

(42 citation statements)

References 51 publications

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“…19). The IC 50 value for A939572 was determined using a recombinant microsome desaturation assay that measures formation of tritiated water upon desaturation of stearic acid labeled with tritium at C9 and C10 (17,20,21). The IC 50 value for A939572 was found to be 6.3 nmol/L in human SCD1 expressing microsomes.…”

Section: Pharmacologic Inhibition Of Scd1 Results In Serumdependent Rmentioning

confidence: 99%

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Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy

Roongta

Pabalan

Wang

et al. 2011

Molecular Cancer Research

227

199

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Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that desaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy. Mol Cancer Res; 9(11); 1551-61. Ó2011 AACR.

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Section: Pharmacologic Inhibition Of Scd1 Results In Serumdependent Rmentioning

confidence: 99%

“…In vitro SCD1 activity was determined using a modified version of the assay described by Obukowicz and colleagues (17). Microsomes were prepared from Sf9 insect cells coexpressing recombinant human SCD1 and Cytochrome b5/ b5R.…”

Section: Scd Activity Determinationmentioning

confidence: 99%

Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy

Roongta

Pabalan

Wang

et al. 2011

Molecular Cancer Research

227

199

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“…Hepatocytes were incubated with CP-24879, a specific Δ5/Δ6 desaturase inhibitor,17 CAY10566, a selective Δ9 desaturase inhibitor,18 EPA or resolvin D1 (RvD1) as detailed in online supplementary material and methods.…”

Section: Methodsmentioning

confidence: 99%

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis

López‐Vicario

González-Périz

Rius

et al. 2013

Gut

114

108

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Objective The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH. Design and results Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes. Conclusions These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.

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“…The most signifi cant association was between the SNP rs174537 (fl ap endonuclease 1, FEN1 10154G>T) near FADS1 and the analysis of arachidonic acid (AA, 20:4 6). AA is synthesized primarily in the liver and then mobilized to infl ammatory cells via blood lipoproteins ( 16 ). AA is the precursor of prostaglandins, leukotrienes, and related compounds, all of which have important roles in infl ammation (17)(18)(19).…”

Section: Urinary 8-epi-pgf 2 ␣ and Plasma Mdamentioning

confidence: 99%

Interactions between the APOA5 -1131T>C and the FEN1 10154G>T polymorphisms on ω6 polyunsaturated fatty acids in serum phospholipids and coronary artery disease

Park

Paik

Kim

et al. 2010

Journal of Lipid Research

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The apolipoprotein A5 gene ( APOA5 ) is predominantly expressed in the liver and secreted into the blood where it resides on HDL and VLDL particles ( 1 ). Despite its very low levels in plasma, apoA5 appears to facilitate the interaction between circulating lipoprotein particles and proteoglycans on the vascular wall with the subsequent activation of proteoglycan-bound lipoprotein lipase ( 2-4 ). The APOA5 -1131T>C single nucleotide polymorphism (SNP) has been reported to be functional and is associated with reduced apoA5 concentration or activity ( 5 ). In particular, the APOA5 -1131C variant allele modulates the effects of dietary PUFA intake on fasting triglyceride levels, lipoprotein particle size ( 6 ), and obesity ( 7 ) and PUFA-APOA5 interactions are specifi c for dietary 6 PUFAs. The fatty acid composition of serum phospholipids mirrors dietary fatty acid intake over previous weeks and also refl ects Abstract We determined the contribution of the combination of FEN1 10154G>T with the most signifi cant association in the analysis of plasma arachidonic acid (AA, 20:4 6) and the APOA5 -1131T>C on phospholipid 6PUFA and coronary artery disease (CAD). Patients with CAD (n = 807, 27-81 years of age) and healthy controls (n = 1123) were genotyped for FEN1 10154G>T and APOA5 -1131T>C. We found a signifi cant interaction between these two genes for CAD risk ( P = 0.007) adjusted for confounding factors. APOA5 -1131C allele carriers had a higher CAD risk [odds ratio (OR):1.484, 95% confi dence interval (CI):1.31-1.96; P = 0.005] compared with APOA5 -1131TT individuals in the FEN1 10154GG genotype group but not in the FEN1 10154T allele group (OR:1.096, 95%CI:0.84-1.43; P = 0.504). Signifi cant interactions between these two genes were also observed for the AA proportion ( P = 0.04) and the ratio of AA/ linoleic acid (LA, 18:2 6) ( P = 0.004) in serum phospholipids of controls. The APOA5 -1131C allele was associated with lower AA ( P = 0.027) and AA/LA ( P = 0.014) only in controls carrying the FEN1 10154T allele. In conclusion, the interaction between these genes suggests that the FEN1 10154T variant allele decreases AA and AA/LA in the serum phospholipids of carriers of the APOA5 -1131C allele, but contributes no signifi cant increase in CAD risk for this population subset despite their increased triglylcerides and decreased

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Identification and Characterization of a Novel Δ6/Δ5 Fatty Acid Desaturase Inhibitor As a Potential Anti-Inflammatory Agent

Cited by 53 publications

References 51 publications

Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy

Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis

Interactions between the APOA5 -1131T>C and the FEN1 10154G>T polymorphisms on ω6 polyunsaturated fatty acids in serum phospholipids and coronary artery disease

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