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.

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 Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver

Metabolomics ◽  
2020 ◽  
Vol 16 (1) ◽  
Author(s):  
David Balgoma ◽  
Sofia Zelleroth ◽  
Alfhild Grönbladh ◽  
Mathias Hallberg ◽  
Curt Pettersson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Metabolic Diseases ◽  
De Novo ◽  
High Resolution Mass Spectrometry ◽  
De Novo Lipogenesis ◽  
Anabolic Androgenic Steroids ◽  
Lipid Profiling ◽  
Testosterone Undecanoate ◽  
Androgenic Steroids

Abstract Introduction The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown. Objectives To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver. Methods We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry. Results Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid. Conclusion The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

scholarly journals Risk of diabetes associated with fatty acids in the de novo lipogenesis pathway is independent of insulin sensitivity and response: the Insulin Resistance Atherosclerosis Study (IRAS)

2019 ◽  
Vol 7 (1) ◽  
pp. e000691 ◽  
Author(s):  
Waqas Qureshi ◽  
Ingrid D Santaren ◽  
Anthony J Hanley ◽  
Steven M Watkins ◽  
Carlos Lorenzo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Diabetes Incidence ◽  
Incident Type ◽  
Insulin Resistance Atherosclerosis Study

ObjectiveTo examine the associations of fatty acids in the de novo lipogenesis (DNL) pathway, specifically myristic acid (14:0), palmitic acid (16:0),cis-palmitoleic acid (c16:1 n-7),cis-myristoleic acid (c14:1n5), stearic acid (18:0) andcis-oleic acid (c18:1 n-9), with 5-year risk of type 2 diabetes. We hypothesized that DNL fatty acids are associated with risk of type 2 diabetes independent of insulin sensitivity.Research design and methodsWe evaluated 719 (mean age 55.1±8.5 years, 44.2% men, 42.3% Caucasians) participants from the Insulin Resistance Atherosclerosis Study. Multivariable logistic regression models with and without adjustment of insulin sensitivity were used to assess prospective associations of DNL fatty acids with incident type 2 diabetes.ResultsType 2 diabetes incidence was 20.3% over 5 years. In multivariable regression models, palmitic, palmitoleic, myristic, myristoleic and oleic acids were associated with increased risk of type 2 diabetes (p<0.05). Palmitic acid had the strongest association (OR per standard unit of palmitic acid 1.46; 95% CI 1.23 to 1.76; p<0.001), which remained similar with addition of insulin sensitivity and acute insulin response (AIR) to the model (OR 1.36; 95% CI 1.09 to 1.70, p=0.01). Oleic and palmitoleic acids were also independently associated with incident type 2 diabetes. In multivariable models, ratios of fatty acids corresponding to stearoyl CoA desaturase-1 and Elovl6 enzymatic activity were significantly associated with risk of type 2 diabetes independent of insulin sensitivity and AIR.ConclusionsWe observed associations of DNL fatty acids with type 2 diabetes incidence independent of insulin sensitivity.

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.

scholarly journals Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies

PLoS Medicine ◽  
2020 ◽  
Vol 17 (6) ◽  
pp. e1003102 ◽  
Author(s):  
Fumiaki Imamura ◽  
Amanda M. Fretts ◽  
Matti Marklund ◽  
Andres V. Ardisson Korat ◽  
Wei-Sin Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Cohort Studies ◽  
Prospective Cohort ◽  
De Novo ◽  
Pooled Analysis ◽  
De Novo Lipogenesis ◽  
Prospective Cohort Studies

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.

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.

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