Fatty Acid Desaturation Index Research Articles

TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES

Abstract Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids, is often upregulated in breast cancer brain metastasis (BCBM) and is considered a promising therapeutic target. However, the lack of brain penetrant SCD inhibitors limited their use in patients. This study aimed to investigate the therapeutic efficacy of a clinical-stage brain penetrant inhibitor of SCD to treat BCBM. We found that pharmacologic inhibition of SCD in multiple breast cancer cell lines induced significant cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed that the fatty acid desaturation index, which measures SCD activity, was significantly lower after treatment. SCD inhibition triggered endoplasmic reticulum (ER) stress and increased DNA damage due to a higher production of reactive oxygen species. Further, SCD inhibition decreased DNA damage repair by inhibiting homology-directed repair in vitro and in a mouse model of breast cancer. Notably, inhibition of SCD led to a significant decrease in tumor growth in a subcutaneous mouse model of breast cancer and a significant increase in overall survival in a BCBM mouse model. Cytotoxicity was enhanced when this SCD inhibitor was combined with either a DNA damage-inducing agent (temozolomide or radiation) or with a PARP inhibitor (Niraparib). Finally, we observed that combination therapy of SCD inhibition and Niraparib significantly increased overall survival in a BCBM mouse model. Our results suggest that inhibition of SCD alone or in combination with a PARP inhibitor is a promising therapeutic strategy to treat BCBM.

Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson\u2019s Disease

SummaryStearoyl-CoA desaturase (SCD) is a potential therapeutic target for Parkinson’s and related neurodegenerative diseases. SCD inhibition ameliorates neuronal toxicity caused by aberrant α-synuclein, a lipid-binding protein implicated in Parkinson’s disease. Its inhibition depletes monounsaturated fatty acids, which may modulate α-synuclein conformations and membrane interactions. Herein, we characterize the pharmacokinetic and pharmacodynamic properties of YTX-7739, a clinical-stage SCD inhibitor. Administration of YTX-7739 to rats and monkeys for 15 days caused a dose-dependent increase in YTX-7739 concentrations that were well-tolerated and associated with concentration-dependent reductions in the fatty acid desaturation index (FADI), the ratio of monounsaturated to saturated fatty acids. An approximate 50% maximal reduction in the carbon-16 desaturation index was observed in the brain, with comparable responses in the plasma and skin. A study with a diet supplemented in SCD products indicates that changes in brain C16 desaturation were due to local SCD inhibition, rather than to changes in systemic fatty acids that reach the brain. Assessment of pharmacodynamic response onset and reversibility kinetics indicated that approximately 7 days of dosing were required to achieve maximal responses, which persisted for at least 2 days after cessation of dosing. YTX-7739 thus achieved sufficient concentrations in the brain to inhibit SCD and produce pharmacodynamic responses that were well-tolerated in rats and monkeys. These results provide a framework for evaluating YTX-7739 pharmacology clinically as a disease-modifying therapy to treat synucleinopathies.

The role of stearoyl-CoA desaturase in the regulation of cardiac metabolism.

The uptake and utilization of energetic substrates in the myocardium are under strict control, any disturbances of which may lead to myocardial dysfunction, such as in the case of ischemia and heart failure. Stearoyl-CoA desaturase (SCD) is an enzyme that converts saturated fatty acids to monounsaturated fatty acids. It is an important player in the regulation of heart metabolism. Our previous studies showed that SCD1 affects substrate utilization by the heart, with a preference for glucose. Large cohort studies established a positive correlation between the plasma fatty acid desaturation index and cardiovascular disease mortality. Therefore, SCD1 might serve as a potential target for future therapies. We review recent findings on the role of SCD1 in the heart, with a focus on cardiac metabolism reprogramming and its involvement in heart dysfunction.

Long-term dietary supplementation with saury oil attenuates metabolic abnormalities in mice fed a high-fat diet: combined beneficial effect of omega-3 fatty acids and long-chain monounsaturated fatty acids.

BackgroundPacific saury is a common dietary component in East Asia. Saury oil contains considerable levels of n-3 unsaturated fatty acids (PUFA) and long-chain monounsaturated fatty acids (LCMUFA) with aliphatic tails longer than 18 carbons. In our previous study, consumption of saury oil for 4 to 6 wk improved insulin sensitivity and the plasma lipid profile in mice. However, the long-term effects of saury oil on metabolic syndrome (MetS) risk factors remain to be demonstrated. In the current study, we examined the long-term effects of saury oil on mice fed a high-fat diet, and compared the effect of n-3 PUFA EPA and LCMUFA on MetS risk factor in diet-induced obese mice.Methods and ResultsIn Experiment 1, male C57BL/6 J mice were fed either a 32 % lard diet (control) or a diet containing 22 % lard plus 10 % saury oil (saury oil group) for 18 weeks. Although no differences were found in body weight and energy expenditure between the control and saury oil groups, the saury oil diet decreased plasma insulin, non–HDL cholesterol, hepatic steatosis, and adipocyte size, and altered levels of mRNA transcribed from genes involved in insulin signaling and inflammation in adipose tissue. Organ and plasma fatty acid profile analysis revealed that consumption of saury oil increased n-3 PUFA and LCMUFA (especially n-11 LCMUFA) levels in multiple organs, and decreased the fatty acid desaturation index (C16:1/C16:0; C18:1/C18:0) in liver and adipose tissue. In Experiment 2, male C57BL/6 J mice were fed a 32 % lard diet (control), a diet containing 28 % lard plus 4 % EPA (EPA group), or a diet containing 20 % lard plus 12 % LCMUFA concentrate (LCMUFA group) for 8 weeks. EPA or LCMUFA intake increased organ levels of EPA and LCMUFA, respectively. Consumption of EPA reduced plasma lipid levels and hepatic lipid deposition, and decreased the fatty acid desaturation index in liver and adipose tissue. Consumption of LCMUFA decreased plasma non–HDL cholesterol, improved hyperinsulinemia, and decreased the fatty acid desaturation index in adipose tissue. EPA accumulated mainly in liver, and LCMUFA (especially n-11 LCMUFA) accumulated mainly in white adipose tissue, suggesting their possible individual biological effects for improving MetS.ConclusionOur results suggest that saury oil-mediated improvement of metabolic syndrome in diet-induced obese mice may possibly be due to a combined effect of n-3 PUFA and LCMUFA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-015-0161-8) contains supplementary material, which is available to authorized users.

Visceral and subcutaneous adipose tissue stearoyl‐CoA desaturase‐1 mRNA levels and fatty acid desaturation index positively correlate with BMI in morbidly obese women

The aim of this study was to re‐evaluate possible associations between BMI and (1) stearoyl‐CoA desaturase‐1 (SCD1) gene expression in adipose tissue; (2) adipose tissue or serum lipids oleic acid/stearic acid (18:1/18:0) desaturation index (DI); and (3) expression of less studied SCD isoform SCD5 in adipose tissue of obese patients. SCD1 and SCD5 mRNA levels in adipose tissue from 16 morbidly obese women were analyzed by RT‐PCR. Fatty acid composition of adipose tissue and whole serum lipids were determined with gas chromatography‐mass spectrometry. The SCD1 mRNA levels, as well as 18:1/18:0 DI in adipose tissue, correlated positively with BMI in obese patients. A weak positive association between the serum lipid 18:1/18:0 DI and BMI did not reach the threshold of statistical significance. The SCD5 mRNA levels in adipose tissue were approximately 400 times lower than the SCD1 levels and did not correlate with BMI. Positive correlations between BMI and visceral or subcutaneous adipose tissue 18:1/18:0 DI were stronger than the association between serum whole lipid 18:1/18:0 DI and BMI in morbidly obese women. The expression of the SCD1 gene in human adipose tissue is markedly stronger than the expression of the SCD5 gene.Practical applications: Our findings confirm previous suggestions that SCD1 may serve as an attractive therapeutic target in patients with obesity and related disorders.Oleic acid/stearic acid (18:1/18:0) desaturation index (DI) in adipose tissue of obese subjects reflects the level of SCD1 gene expression in adipose tissue. Positive correlations between BMI and adipose tissue DI were stronger than the association between serum whole lipid DI and BMI in morbidly obese women.

4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.

Tissue fatty acid composition in obstructive sleep apnea and recurrent tonsillitis

ObjectiveTonsillar hypertrophy cells appear to have an altered lipid metabolism as evidenced by modulated inflammatory cytokines that affect tissue lipid metabolism. The aim of this study was to investigate differences in tissue fat composition between obstructive sleep apnea (OSA) and recurrent infective tonsillitis (RT) in children. MethodsTonsillar tissues were collected from 114 patients with OSA and 92 patients with RT, aged 4–10 years, during tonsillectomy. The tissue lipid extracts were analyzed by gas liquid chromatography for a comprehensive fatty acid profile. ResultsIn the tonsillitis tissue, the levels of palmitoleic acid (16:1n−7; P=0.002) and oleic acid (18:1n−9; P=0.003) were higher, and the level of stearic acid (18:0; P=0.004) was lower than that in the hyperplastic tonsillar tissue. Overall, tonsillar tissue of patients with RT had a significant increase in the total monounsaturated fatty acids (+9.9%; P<0.001) and the fatty acid desaturation index (+20.5%; P<0.001). Furthermore, oleic acid content of tonsillar tissue was positively correlated with BMI (r=0.20, P=0.004), snoring (r=0.16, P=0.022) and hypertrophy grade (r=0.18, P=0.023), which remain significant in the subgroup analysis by hypertrophy type. ConclusionsThe change in the fatty acid composition may be regarded as an indicator of altered lipid metabolism occurring in vivo during human tonsillar hypertrophy, which might be linked to the severity or type of the tissue damage.

Management of Severe Hypertriglyceridemia with a Novel Omega-3 Free- Fatty Acid Formulation: Subgroups in the EVOLVE Trial

s 271 LDL-C: 83 mg/dL). Relative to baseline and compared with placebo, IPE 4 g/day was found to significantly reduce median TG (primary endpoint), and to reduce LDL-C and apolipoprotein B (ApoB) (secondary endpoints). Purpose: To determine the effects of IPE in the ANCHOR study on: the exploratory endpoints of lipoprotein particle concentration; the correlation with ApoB; and the fatty acid desaturation index (FADI), a biomarker of hepatic stearoylCoA desaturase (SCD) activity (the key enzyme involved in the synthesis of monounsaturated fatty acids from saturated fatty acids). FADI can assess SCD activity, which has clinical relevance to TG levels, cardiovascular disease, metabolic disease, and certain cancers. Methods: ANCHOR(N5 702)was a phase 3,multicenter, placebo-controlled, randomized, double-blind, 12-week study. Lipoprotein particle concentration was measured by nuclear magnetic resonance spectroscopy. The FADI (eg, the ratios of palmitoleic acid to palmitic acid [C16:1/C16:0] and oleic acid to stearic acid [C18:1/C18:0]) was examined in plasma and red blood cells (RBCs). Results: Relative to baseline and compared with placebo, IPE4g/day significantly reducedmedianconcentrationsof total very-low-density lipoprotein (VLDL; 12.2%, P, 0.001), total LDL (7.7%,P,0.01), total high-density lipoprotein (7.4%,P, 0.0001), and small LDL particles (13.5%, P , 0.0001). Atherogenic lipoprotein particle (total VLDL and total LDL) OM3-FFA 2 grams/day (N537) OM3Diabetes BL %Change LS Mean %Change Median BL TG 749 -29 -26 639 Non-HDL-C 195 -12 -11 211

Effects of Icosapent Ethyl on Lipoprotein Particle Concentration and the Fatty Acid Desaturation Index in Statin-treated Patients With Persistent High Triglycerides (the ANCHOR Study)

Dr. Ballantyne has been a consultant to Abbott Laboratories, Adnexus, and Amarin Corp.

Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.

Inhibition of MEK/ERK1/2 Signaling Affects the Fatty Acid Composition of HepG2 Human Hepatic Cell Line.

The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, also known as the MEK/ERK1/2 kinase cascade, has recently been implicated in the regulation of lipid metabolism and fatty liver disease. However, its functional effect on cellular fatty acid composition is unknown. Herein, we examined the effect of a pharmacological inhibitor of MEK, the upstream kinase activator of ERK1/2, on fatty acid composition of hepatocellular carcinoma cell line HepG2. HepG2 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and were investigated with respect to fatty acid composition by gas-liquid chromatography. Exposure of cells to the ERK1/2 pathway inhibitor induced an increase in monounsaturated fatty acids and the fatty acid desaturation index and a decrease in polyunsaturated fatty acid content. Specifically, we showed a significant increase of oleic acid (18:1n-9; +29%, P=0.003) and arachidonic acid (20:4n-6)/linoleic acid (18:2n-6) ratio (3.5-fold; P<0.001) in HepG2 cells. Cellular fatty acid composition of HepG2 cells appeared to be differentially regulated by ERK1/2 pathway, thus suggesting related metabolic pathways as potential mediators of the effects of ERK1/2 signaling on hepatic fatty acid composition.

The fatty acid desaturation index of blood lipids, as a biomarker of hepatic stearoyl-CoA desaturase expression, is a predictive factor of breast cancer risk

This review summarizes epidemiological data linking the fatty acid desaturation index measured in blood lipids, as a biomarker of hepatic stearoyl-CoA desaturase activity, the key enzyme involved in the synthesis of monounsaturated fatty acids from saturated fatty acids, to breast cancer risk. The biological plausibility of this association is discussed. Epidemiological cohort studies reported an association between a high saturated to monounsaturated fatty acid ratio measured in blood lipids, indicating low stearoyl-CoA desaturase-1 activity, and decreased breast cancer risk. The suppression of stearoyl-CoA desaturase expression reduces cancer cell proliferation and in-vitro invasiveness, and dramatically impairs tumor formation and growth. These effects could not be overcome by supplying exogenous monounsaturated fatty acids. Epidemiological findings, in accordance with experimental data, suggested that decreased hepatic stearoyl-CoA desaturase expression/activity may be related to decreased risk of breast cancer.

The Δ9 Fatty Acid Desaturation Index as a Predictor of Metabolic Disease

There is a tremendous need for improved biomarkers that can be used in the clinical setting to aid in the early detection of metabolic diseases. Of particular interest is the metabolic syndrome, or insulin resistance syndrome, a condition that is often clinically diagnosed as a cluster of risk factors including abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, impaired glucose tolerance, and increased fasting glucose (1)(2). This constellation of phenotypes greatly increases the risk for the development of chronic conditions such as diabetes and several cardiovascular diseases. The root cause of the metabolic syndrome is insulin resistance, a condition in which the pancreas increases insulin secretion to compensate for the decreased ability of insulin-sensitive tissues to perform insulin-stimulated glucose uptake to maintain euglycemia (1). Therefore, the development of new tests that focus on the early detection of insulin resistance could help identify at-risk patients so that the benefits of lifestyle and pharmacological interventions can be maximized and progression to overt metabolic disease can be prevented. Insulin resistance is not limited to defects in carbohydrate metabolism, but is also associated with major perturbations in lipid metabolism (2). For example, adipocytes increase the release of free fatty acids (FFA)1 into the circulation, resulting in subsequent FFA uptake by the liver and other peripheral tissues, processes that may further exacerbate insulin resistance (2)(3). Although hepatic insulin resistance contributes to hyperglycemia by causing an inappropriate elevation in hepatic glucose production, the branch of insulin signaling responsible for stimulating de novo fatty acid biosynthesis in the liver remains intact (2)(4). Additionally, high-carbohydrate diets, especially those enriched in rapidly absorbed refined carbohydrates such as glucose and fructose, are able to potently stimulate de novo lipogenesis (DNL) (5). The effects of insulin and dietary carbohydrate occur via the transcriptional activation of …

Fatty acid desaturation index correlates with body mass and adiposity indices of obesity in Wistar NIN obese mutant rat strains WNIN/Ob and WNIN/GR-Ob

BackgroundMicrosomal stearoyl-CoA desaturase1 (SCD1) is the rate limiting enzyme involved in the biosynthesis of monounsaturated fatty acids (MUFAs); palmitoleic (16:1) and oleic (18:1) acid from their respective substrates palmitic (16:0) and stearic (18:0) acids. The ratio of 18:1 to 18:0 has been implicated in the regulation membrane fluidity and function. SCD1 is abundantly expressed in obese humans as well as rodent models. However, no studies have correlated the fatty acid desaturation index (16:1/16:0 and 18:1/18:0), an indicator of SCD1 activity with the markers of obesity in terms of body mass index (BMI) and adiposity index (AI). Therefore, here, we attempted to relate the fatty acid desaturation index with BMI and AI in Wistar NIN-obese mutant rat strains namely, WNIN/Ob and WNIN/GR-Ob (with impaired glucose tolerance).MethodsFor this purpose, 200 days old male 6 lean and 6 obese rats of both strains were taken. Fatty acid composition was analyzed in plasma, various tissues such as liver, white adipose tissues (retroperitoneal, epididymal, omental, and subcutaneous) and brown adipose tissue.ResultsFatty acid composition data showed significant increase in palmitoleic (16:1) and oleic (18:1) acid levels, which were reflected in increased desaturation index (16:1/16:0 and 18:1/18:0) in plasma and all the tissues of obese rats of both strains, when compared with their respective age and sex-matched lean rats. Further, we found a strong positive correlation between desaturation index, BMI and AI in plasma and most of the tissues analyzed.ConclusionSo far, plasma Δ9 desaturation index has been well correlated with hypertriglyceridemia and we, by employing two models of obesity namely, WNIN/Ob and WNIN/GR-Ob, have shown Δ9 desaturation index of plasma correlated with physical markers of obesity such as BMI and AI. In conclusion, Δ9 desaturation index may serve as a potential sensitive biochemical marker to assess the degree of obesity and impact of therapeutic/nutritional interventions to combat obesity, along with other indicators.

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (P < 0.0001). The fatty acid desaturation index was found to be highly heritable (h(2) = 0.48, P = 2.2 x 10(-11)) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (z = 2.7, P = 0.003), containing the peroxisome proliferator-activated receptor gamma (PPARgamma) gene, and 20p11.21 to 20q13.32 (z = 1.7, P = 0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4alpha) gene. A specific haplotype of HNF4alpha was found to be associated with the desaturation index in these FCHL families (P = 0.002). Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL.

Genetic variation in fatness and fatty acid composition of crossbred cattle.

Mature Hereford cows (766) were mated to 97 sires from seven breeds (Jersey, Wagyu, Angus, Hereford, South Devon, Limousin, and Belgian Blue), resulting in 1,215 calves born over 4 yr (1994 to 1997). These cattle comprised Australia's 'Southern Crossbreeding Project." Heifers were slaughtered at an average of 16 mo with hot standard carcass weight of 219 kg and 9 mm fat over the rump. Steers were slaughtered at an average of 23 mo with carcass weight of 319 kg and 13 mm fat over the rump. Meat and fat samples were taken from the carcass on the day after slaughter for subsequent laboratory analysis of i.m. fat content and fatty acid composition. Data were analyzed using uni- and bivariate animal models containing fixed effects of cohort, management group, birth month, and sire breed. March-born calves had fat with a 0.5 degrees C lower melting point, 0.6% higher total monounsaturated fatty acids, and 0.7% higher fatty acid desaturation index than calves born in April. Steers born in 1997 were the only cohort finished on pasture, and they had much more yellow fat than the other cohorts. Four heavy breed crosses (Angus, South Devon, Limousin, and Belgian Blue) averaged 284 kg carcass weight, followed by purebred Hereford (268 kg), Wagyu (244 kg) and Jersey (236 kg). Angus had the greatest fat depth (14.3 mm), ahead of Hereford and Wagyu (11.9 mm), Jersey (10.7 mm), South Devon and Limousin (9.9 mm) and Belgian Blue (8.0 mm). Jersey, Wagyu, and Angus had themost i.m. fat (4.6%), followed by Hereford and South Devon (3.8%), and Limousin and Belgian Blue (3.1%). The highly marbled Jersey and Wagyu had softer fat (6% lower fat melting point) than the other breeds. Angus were more highly marbled, similar to Jersey and Wagyu, but had harder fat similar to the leaner breeds. Heritabilities for all traits were low to moderate (16 to 36%). Genetic correlations between fatty add composition and carcass traits were not significant, indicating little evidence of antagonisms between traits that would prevent genetic progress in both production and quality.