scholarly journals Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

2012 ◽  
Vol 303 (5) ◽  
pp. E624-E634 ◽  
Author(s):  
Vidya Vaidyanathan ◽  
Raul A. Bastarrachea ◽  
Paul B. Higgins ◽  
V. Saroja Voruganti ◽  
Subhash Kamath ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Body Weight ◽  
Fatty Acid ◽  
Nonhuman Primates ◽  
Cannabinoid Receptor ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Glucose Disposal ◽  
Before And After

The goal of this study was to determine whether administration of the CB1 cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons ( Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d31-tripalmitin) and intravenously (13C4-palmitate, 13C1-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals ( P < 0.04), glucose disposal increased 30% ( P = 0.03), and FFA turnover increased 37% ( P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg−1·h−1, P = 0.03). These data support the potential for a strong effect of CB1 receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.

EXTH-27. MOLECULAR CHARACTERIZATION AND PRECLINICAL DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITOR SPECIFIC FOR WILD-TYPE IDH1 FOR FERROPTOSIS INDUCTION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi169-vi169
Author(s):  
Kevin Murnan ◽  
Serena Tommasini-Ghelfi ◽  
Lisa Hurley ◽  
Corey Dussold ◽  
Daniel Wahl ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Unsaturated Fatty Acids ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Therapeutic Modality ◽  
Wild Type ◽  
Genetic Ablation

Abstract Increased de novo synthesis, mobilization and uptake of fatty acids are required to provide sufficient lipids for membrane biogenesis in support of rapid tumor cell division and growth. In addition to their structural roles as components of the plasma membrane, fatty acid-derived lipids regulate ferroptotic cell death, a type of programmed cell death, when oxidized by iron-dependent lipoxygenase enzymes. De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that HGG up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high HGG’) to generate large quantities of cytosolic NADPH. RNAi-mediated knockdown of wt-IDH1, alone and in combination with radiation therapy (RT), slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Isotope tracer and liquid chromatography-based lipidomic studies indicated that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs) and promotes the incorporation of monounsaturated phospholipids into the plasma membrane, while displacing polyunsaturated fatty acid (PUFA) phospholipids. In addition, enhanced NADPH production in wt-IDH1high HGG increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, and dampens the accumulation of PUFA-containing lipid peroxides, known executioners of ferroptosis. To pharmacologically target wt-IDH1,we have used and characterized wt-IDH1i-13, a first-in-class competitive α,β-unsaturated enone (AbbVie). wt-IDH1i-13 potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that wt-IDH1i-13 promotes ferroptosis, which can be rescued by pre-treatment of cells with the peroxyl scavenger and ferroptosis inhibitor ferrostatin. wt-IDH1i-13 is brain-penetrant, and similar to genetic ablation, reduces progression and extends the survival of wt-IDH1high HGG bearing mice, alone and in combination with RT. These studies credential to wt-IDH1i-13 as a novel therapeutic modality for the treatment of wt-IDH1 gliomas.

scholarly journals Sterol regulatory element binding protein and dietary lipid regulation of fatty acid synthesis in the mammary epithelium

2010 ◽  
Vol 299 (6) ◽  
pp. E918-E927 ◽  
Author(s):  
Michael C. Rudolph ◽  
Jenifer Monks ◽  
Valerie Burns ◽  
Meridee Phistry ◽  
Russell Marians ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Sterol Regulatory Element

The lactating mammary gland synthesizes large amounts of triglyceride from fatty acids derived from the blood and from de novo lipogenesis. The latter is significantly increased at parturition and decreased when additional dietary fatty acids become available. To begin to understand the molecular regulation of de novo lipogenesis, we tested the hypothesis that the transcription factor sterol regulatory element binding factor (SREBF)-1c is a primary regulator of this system. Expression of Srebf1c mRNA and six of its known target genes increased ≥2.5-fold at parturition. However, Srebf1c-null mice showed only minor deficiencies in lipid synthesis during lactation, possibly due to compensation by Srebf1a expression. To abrogate the function of both isoforms of Srebf1, we bred mice to obtain a mammary epithelial cell-specific deletion of SREBF cleavage-activating protein (SCAP), the SREBF escort protein. These dams showed a significant lactation deficiency, and expression of mRNA for fatty acid synthase ( Fasn), insulin-induced gene 1 ( Insig1), mitochondrial citrate transporter ( Slc25a1), and stearoyl-CoA desaturase 2 ( Scd2) was reduced threefold or more; however, the mRNA levels of acetyl-CoA carboxylase-1α ( Acaca) and ATP citrate lyase ( Acly) were unchanged. Furthermore, a 46% fat diet significantly decreased de novo fatty acid synthesis and reduced the protein levels of ACACA, ACLY, and FASN significantly, with no change in their mRNA levels. These data lead us to conclude that two modes of regulation exist to control fatty acid synthesis in the mammary gland of the lactating mouse: the well-known SREBF1 system and a novel mechanism that acts at the posttranscriptional level in the presence of SCAP deletion and high-fat feeding to alter enzyme protein.

Effects of pregnancy and ovarian steroids on fatty acid synthesis and uptake in Syrian hamsters

1991 ◽  
Vol 260 (1) ◽  
pp. R153-R158 ◽  
Author(s):  
A. J. Bhatia ◽  
G. N. Wade
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
White Adipose Tissue ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Ovarian Steroids ◽  
Syrian Hamsters

The effects of pregnancy and ovarian steroids on the in vivo distribution of newly synthesized fatty acids (incorporation of tritium from 3H2O into fatty acid) in Syrian hamsters (Mesocricetus auratus) were examined. During late, but not early, gestation hamsters had reduced levels of newly synthesized fatty acids in heart, liver, uterus, and white adipose tissues (parametrial and inguinal fat pads). Treatment of ovariectomized hamsters with estradiol + progesterone significantly decreased fatty acid synthesis-uptake in heart, liver, and inguinal white adipose tissue. Treatment with either estradiol or progesterone alone was without significant effect in any tissue. Pretreatment of hamsters with Triton WR-1339 (tyloxapol), an inhibitor of lipoprotein lipase activity and tissue triglyceride uptake, abolished the effects of estradiol + progesterone in white adipose tissue and heart but not in liver. Thus hamsters lose body fat during pregnancy in part because of decreased de novo lipogenesis. The effect of pregnancy on lipogenesis is mimicked by treatment with estradiol + progesterone but not by either hormone alone. Furthermore, it appears that the liver is the principal site of estradiol + progesterone action on lipogenesis in Syrian hamsters.

Abstract 12: Prospective Associations of Fatty Acids in the De Novo Lipogenesis Pathway and Stearoyl CoA-desaturase-1 Activity with Risk of Type 2 Diabetes: the Cardiovascular Health Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Wenjie Ma ◽  
Jason H Wu ◽  
Qianyi Wang ◽  
Rozenn N Lemaitre ◽  
Kenneth J Mukamal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Fatty Acids ◽  
Fatty Acid ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Metabolic Risk ◽  
Secondary Analyses ◽  
Stearoyl Coa Desaturase ◽  
Fatty Acid Biomarkers

Background: Experimental evidence suggests de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated (SFA) and monounsaturated fatty acids (MUFA), and also through altered activity of the key regulatory enzyme, Stearoyl-CoA desaturase-1 (SCD-1). Only limited studies have utilized biomarkers of SFA, MUFA and estimated SCD-1 activity to assess their prospective association with risk of type 2 diabetes (T2D). Objective: To investigate the association of 3 major circulating SFA (palmitic acid,16:0, stearic acid,18:0) and MUFA (oleic acid,18:1n-9) in the DNL pathway with metabolic risk factors and incident T2D in a community based cohort of US adults (aged≥65y). In secondary analyses, we assessed relations of other fatty acid biomarkers in the DNL pathway (14:0, 16:1n-7, 16:1n-9, 18:1n-7, and SCD-1 activity estimated by 16:1n-7/16:0 and 18:1n-9/18:0), as well as dietary intake of individual SFA and MUFA with incident T2D. Methods: Among 3060 participants free of T2D and with plasma phospholipid fatty acid measures in 1992 (study baseline), incident T2D cases were identified by medication use assessed annually and repeated blood glucose measures. Usual dietary habits were assessed by repeated FFQs. Associations of fatty acids with metabolic risk factors and incident diabetes were evaluated by multivariate linear regression and Cox proportional models, respectively. Results: During 30,763 person-years of follow-up, 353 incident cases were identified. Higher circulating 16:0 and 18:0 were associated with adverse metabolic profiles including greater BMI, inflammation biomarkers and HOMA-IR (P-trend<0.01 for each), whereas higher 18:1n-9 showed generally beneficial associations (P-trend<0.001 for each). After adjustment for demographic and lifestyle factors, a higher risk of T2D was seen for 16:0 (quintile 5 vs. 1 HR 2.39, 95% CI 1.65-3.46, P-trend<0.001) and 18:0 (HR 1.48, 95% CI 1.04-2.11, P-trend=0.009), but not for 18:1n-9 (HR 0.87, 95% CI 0.59-1.27, P-trend=0.77). In secondary analyses, 16:1n-7 (HR 1.50, 95% CI 1.03-2.20, P-trend=0.03) was positively associated while 18:1n-7 (HR 0.50, 95% CI 0.35-0.72, P-trend<0.001) was inversely associated with risk of T2D. Other fatty acid biomarkers, estimated SCD-1 activity and dietary intake of individual fatty acids, as isocaloric replacement for carbohydrate, were not significantly associated with incident T2D. Conclusion: Circulating levels of 16:0, 18:0 and 16:1n-7 were associated with an increased risk of incident T2D in older adults, whereas 18:1n-7 was associated with lower risk. These results highlight the need for further investigation of biological mechanisms that link specific fatty acids in the DNL pathway to pathogenesis of T2D.

Model for measuring absolute rates of hepatic de novo lipogenesis and reesterification of free fatty acids

1993 ◽  
Vol 265 (5) ◽  
pp. E814-E820 ◽  
Author(s):  
M. K. Hellerstein ◽  
R. A. Neese ◽  
J. M. Schwarz
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
De Novo ◽  
Human Subjects ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Distribution Analysis ◽  
Oxidation Rates ◽  
Mass Isotopomer Distribution Analysis

We have previously presented a precursor-product stable isotopic technique for measuring in vivo the fraction of very low-density lipoprotein-fatty acids (VLDL-FA) derived from de novo lipogenesis (fractional DNL). Here, we propose a technique for converting fractional DNL into absolute rates of DNL and describe its explicit underlying assumptions. The technique combines the fractional DNL method with a modification of the method of S. Klein, V. R. Young, G. L. A. Blackburn, B. R. Bistrain, and R. R. Wolfe (J. Clin. Invest. 78: 928-933, 1986), for estimating hepatic reesterification of free fatty acids (FFA). Infusions of [1,2,3,4-13C]palmitate and [1-13C]acetate are performed concurrently with indirect calorimetry in human subjects. Fractional DNL (based on mass isotopomer distribution analysis of VLDL-FA), the rate of appearance of plasma FFA (Ra of FFA), and net fat oxidation in the whole body are measured. Equations from the hepatic reesterification model, modified to include the contribution from DNL, allow calculation of absolute DNL (= fractional DNL x [Ra of FFA - net whole body fat oxidation], when respiratory quotient < 1.0). Sample results from human subjects with different dietary energy intakes are presented, with calculations of absolute DNL, absolute reesterification, and absolute fat oxidation rates. The assumptions of this technique (in particular, that all fat oxidized is derived at steady state from circulating FFA and that DNL and reesterification of FFA both occur exclusively in liver) are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of regulation of lipogenesis in the Zucker diabetic rat. II. Changes in stearate and oleate synthesis

2002 ◽  
Vol 282 (3) ◽  
pp. E507-E513 ◽  
Author(s):  
Sara Bassilian ◽  
Syed Ahmed ◽  
Shu K. Lim ◽  
Laszlo G. Boros ◽  
Catherine S. Mao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chain Elongation ◽  
High Fat ◽  
Zdf Rat

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat.

scholarly journals A Simplified Scintillation Proximity Assay for Fatty Acid Synthase Activity: Development and Comparison with Other FAS Activity Assays

2009 ◽  
Vol 14 (6) ◽  
pp. 636-642 ◽  
Author(s):  
Nathan W. Bays ◽  
Armetta D. Hill ◽  
Ilona Kariv
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Scintillation Proximity Assay ◽  
Advantages And Disadvantages ◽  
Disease States

Fatty acid synthase (FAS), an essential enzyme for de novo lipogenesis, has been implicated in a number of disease states, including obesity, dyslipidemia, and cancer. To identify small-molecule inhibitors of FAS, the authors developed a bead-based scintillation proximity assay (SPA) to detect the fatty acid products of FAS enzymatic activity. This homogeneous SPA assay discriminates between a radiolabeled hydrophilic substrate of FAS (acetyl-coenzyme A) and the labeled lipophilic products of FAS (fatty acids), generating signal only when labeled fatty acids are present. The assay requires a single addition of unmodified polystyrene imaging SPA beads and can be miniaturized to 384- or 1536-well density with appropriate assay statistics for high-throughput screening. High-potency FAS inhibitors were used to compare the sensitivity of the SPA bead assay with previously described assays that measure FAS reaction intermediates (CoA-SH and NADP +). The advantages and disadvantages of these different FAS assays in small-molecule inhibitor discovery are discussed. ( Journal of Biomolecular Screening 2009:636-642)

Lipid metabolism and adipokine levels in fatty acid-binding protein null and transgenic mice

2006 ◽  
Vol 290 (5) ◽  
pp. E814-E823 ◽  
Author(s):  
Ann V. Hertzel ◽  
Lisa Ann Smith ◽  
Anders H. Berg ◽  
Gary W. Cline ◽  
Gerald I. Shulman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Transgenic Mice ◽  
Fat Mass ◽  
De Novo ◽  
Transgenic Animals ◽  
De Novo Lipogenesis ◽  
Hormone Sensitive Lipase ◽  
Fatty Acid Binding

Fatty acid-binding proteins (FABPs) facilitate the diffusion of fatty acids within cellular cytoplasm. Compared with C57Bl/6J mice maintained on a high-fat diet, adipose-FABP (A-FABP) null mice exhibit increased fat mass, decreased lipolysis, increased muscle glucose oxidation, and attenuated insulin resistance, whereas overexpression of epithelial-FABP (E-FABP) in adipose tissue results in decreased fat mass, increased lipolysis, and potentiated insulin resistance. To identify the mechanisms that underlie these processes, real-time PCR analyses indicate that the expression of hormone-sensitive lipase is reduced, while perilipin A is increased in A-FABP/aP2 null mice relative to E-FABP overexpressing mice. In contrast, de novo lipogenesis and expression of genes encoding lipoprotein lipase, CD36, long-chain acyl-CoA synthetase 5, and diacylglycerol acyltransferase are increased in A-FABP/aP2 null mice relative to E-FABP transgenic animals. Consistent with an increase in de novo lipogenesis, there was an increase in adipose C16:0 and C16:1 acyl-CoA pools. There were no changes in serum free fatty acids between genotypes. Serum levels of resistin were decreased in the E-FABP transgenic mice, whereas serum and tissue adiponectin were increased in A-FABP/aP2 null mice and decreased in E-FABP transgenic animals; leptin expression was unaffected. These results suggest that the balance between lipolysis and lipogenesis in adipocytes is remodeled in the FABP null and transgenic mice and is accompanied by the reprogramming of adipokine expression in fat cells and overall changes in plasma adipokines.

In vivo study of the biosynthesis of long-chain fatty acids using deuterated water

1995 ◽  
Vol 269 (2) ◽  
pp. E247-E252 ◽  
Author(s):  
H. O. Ajie ◽  
M. J. Connor ◽  
W. N. Lee ◽  
S. Bassilian ◽  
E. A. Bergner ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
De Novo ◽  
Chain Elongation ◽  
Deuterated Water ◽  
De Novo Synthesis ◽  
Isotopomer Distribution ◽  
Long Chain ◽  
Mass Isotopomer

To determine the contributions of preexisting fatty acid, de novo synthesis, and chain elongation in long-chain fatty acid (LCFA) synthesis, the synthesis of LCFAs, palmitate (16:0), stearate (18:0), arachidate (20:0), behenate (22:0), and lignocerate (24:0), in the epidermis, liver, and spinal cord was determined using deuterated water and mass isotopomer distribution analysis in hairless mice and Sprague-Dawley rats. Animals were given 4% deuterated water for 5 days or 8 wk in their drinking water. Blood was withdrawn at the end of these times for the determination of deuterium enrichment, and the animals were killed to isolate the various tissues for lipid extraction for the determination of the mass isotopomer distributions. The mass isotopomer distributions in LCFA were incompatible with synthesis from a single pool of primer. The synthesis of palmitate, stearate, arachidate, behenate, and lignocerate followed the expected biochemical pathways for the synthesis of LCFAs. On average, three deuterium atoms were incorporated for every addition of an acetyl unit. The isotopomer distribution resulting from chain elongation and de novo synthesis can be described by the linear combination of two binomial distributions. The proportions of preexisting, chain elongation, and de novo-synthesized fatty acids as a percentage of the total fatty acids were determined using multiple linear regression analysis. Fractional synthesis was found to vary, depending on the tissue type and the fatty acid, from 47 to 87%. A substantial fraction (24-40%) of the newly synthesized molecules was derived from chain elongation of unlabeled (recycled) palmitate.

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