scholarly journals Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5493-5503 ◽  
Author(s):  
Diane C. Lagace ◽  
Roger S. McLeod ◽  
Mark W. Nachtigal
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Weight Gain ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Binding Protein ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Messenger Ribonucleic Acid ◽  
Triacylglycerol Synthesis

Abstract Treatment of epilepsy or bipolar disorder with valproic acid (VPA) induces weight gain and increased serum levels for the satiety hormone, leptin, through an unidentified mechanism. In this study we tested the effects of VPA, a short-chain branched fatty acid (C8:0), on leptin biology and fatty acid metabolism in 3T3-L1 adipocytes. VPA significantly reduced leptin secretion in a dose-dependent manner. Because fatty acid accumulation has been hypothesized to block leptin secretion, we tested the effect of VPA on fatty acid metabolism. Using 14C-radiolabeled VPA, we found that the 14C was mainly incorporated into triacylglycerol. VPA did not alter lipogenesis from acetate, nor did it change the amount of intracellular free fatty acids available for triacylglycerol synthesis. Decreased leptin secretion was accompanied by a reduction in leptin mRNA, even though VPA treatment did not alter the protein levels for known transcription factors affecting leptin transcription including: CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ, or steroid regulatory element binding protein 1a. VPA altered levels of leptin mRNA independent of de novo protein synthesis without affecting leptin mRNA degradation. This report demonstrates that VPA decreases leptin secretion and mRNA levels in adipocytes in vitro, suggesting that VPA therapy may be associated with altered leptin homeostasis contributing to weight gain in vivo.

Abstract 3: The Histone Methyltransferase Smyd1 is a Novel Transcriptional Regulator of Cardiac Fatty Acid Metabolism in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Junko S Warren ◽  
Dane W Barton ◽  
Mickey Miller ◽  
Li Wang ◽  
James Cox ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Cardiac Dysfunction ◽  
Acid Metabolism ◽  
Transcriptional Start Site ◽  
Cardiac Metabolism ◽  
Histone Methyltransferase ◽  
Tamoxifen Treatment ◽  
Mrna Levels

Epigenetic control of metabolism in the healthy and diseased heart remains poorly understood. We recently demonstrated that chromatin-bound Smyd1, a muscle-specific histone methyltransferase, is significantly upregulated in a mouse model of pressure overload-induced heart failure (HF) and that inducible, cardiac-specific Smyd1 knock-out (Smyd1-KO) mice develop cellular hypertrophy and fulminate HF. Bioinformatic analysis of transcripts differentially regulated in these mice revealed that cardiac metabolism was the most perturbed biological function in the heart. However, it was not clear whether alterations in cardiac metabolism were a direct consequence of Smyd1 deletion or were secondary to developed HF. Here we hypothesized that Smyd1 directly regulates cardiac metabolism; the effects of which should be detectable in Smyd1-KO mice before overt cardiac dysfunction. To test this hypothesis we performed unbiased metabolomic analysis of Smyd1-KO mice using GC/MS and MS/MS (n=9 control, n=10 KO) combined with targeted gene expression analysis. Our results showed significant changes in the metabolic profile of Smyd1-KO mice at the earliest time point (3 weeks after tamoxifen treatment) in which Smyd1 protein expression was significantly reduced while cardiac function remained normal. The most profound difference, in energetics-associated pathways in these mice, was found in fatty acid β-oxidation, manifested by the decreased myocardial content of carnitine and free fatty acids and downregulation of their transporters, OCTN2 and CD36. In addition, mRNA levels of the PPAR-α complex (PPAR-α;RXR-α;PGC-1α), an established regulator of fatty acid β-oxidation, and its target genes (CPT1b;CD36;Acox1;MCAD) were significantly reduced in Smyd1-KO mice prior to the onset of cardiac dysfunction (all p<0.05). To identify whether Smyd1 directly controls gene expression of PPAR-α, we examined the PPAR-α loci using chromatin-immunoprecipitation followed by qPCR and observed significant binding of Smyd1 upstream of the PPAR-α transcriptional start site. Overall, this study identifies Smyd1 as a novel regulator of fatty acid metabolism and suggests that Smyd1 controls cardiac energetics directly by regulating gene expression of PPAR-α.

scholarly journals ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

2020 ◽  
Author(s):  
Ada Admin ◽  
Zhuo Mao ◽  
Mingji Feng ◽  
Zhuoran Li ◽  
Minsi Zhou ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Association Studies ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Alcoholic Fatty Liver ◽  
Hepatic Fatty Acid ◽  
Ppar Signaling

ETV5 is an ETS transcription factor which has been associated with obesity in genomic association studies. However, little is known about the role of ETV5 in hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD). In the present study, we found that ETV5 protein expression was increased in diet- and genetic-induced steatotic liver. ETV5 responded to the nutrient status in an mTORC1 dependent manner and in turn regulated mTORC1 activity. Both viral-mediated and genetic depletion of ETV5 in mice led to increased lipid accumulation in the liver. RNA sequencing analysis revealed that PPAR signaling and fatty acid degradation/metabolism pathways were significantly downregulated in ETV5 deficient hepatocytes <i>in vivo</i> and <i>in vitro. </i>Mechanistically, ETV5 could bind to the PPRE region of PPAR downstream genes and enhance its transactivity. Collectively, our study identifies ETV5 as a novel transcription factor for the regulation of hepatic fatty acid metabolism which is required for the optimal β oxidation process. ETV5 may provide a therapeutic target for the treatment of hepatic steatosis.<br>

scholarly journals Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner

Virology ◽  
2019 ◽  
Vol 537 ◽  
pp. 1-13 ◽  
Author(s):  
Zhitao Wang ◽  
Bangyao Sun ◽  
Qi Gao ◽  
Yong Ma ◽  
Yumeng Liang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Cellular Fatty Acid ◽  
Dependent Manner ◽  
Herpesvirus 1 ◽  
Intercellular Spread

Uteroplacental insufficiency alters hepatic fatty acid-metabolizing enzymes in juvenile and adult rats

2001 ◽  
Vol 280 (1) ◽  
pp. R183-R190 ◽  
Author(s):  
Robert H. Lane ◽  
David E. Kelley ◽  
Elisa M. Gruetzmacher ◽  
Sherin U. Devaskar
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Female Rats ◽  
Mrna Levels ◽  
Adult Rats ◽  
Serum Triglycerides ◽  
Hepatic Fatty Acid ◽  
Malonyl Coa

Multiple adult morbidities are associated with intrauterine growth retardation (IUGR) including dyslipidemia. We hypothesized that uteroplacental insufficiency and subsequent IUGR in the rat would lead to altered hepatic fatty acid metabolism. To test this hypothesis, we quantified hepatic mRNA levels of acetyl-CoA carboxylase (ACC), carnitine palmitoyltransferase (CPTI), the β-oxidation-trifunctional protein (HADH), fasting serum triglycerides, and hepatic malonyl-CoA levels at different ages in control and IUGR rats. Fetal gene expression of all three enzymes was decreased. Juvenile gene expression of CPTI and HADH continued to be decreased, whereas gene expression of ACC was increased. Serum triglycerides were unchanged. A sex-specific response was noted in the adult rats. In males, serum triglycerides, hepatic malonyl-CoA levels, and ACC mRNA levels were significantly increased, and CPTI and HADH mRNA levels were significantly decreased. In contrast, the female rats demonstrated no significant changes in these variables. These results suggest that uteroplacental insufficiency leads to altered hepatic fatty acid metabolism that may contribute to the adult dyslipidemia associated with low birth weight.

Abstract 1465: Cardiomyocyte Hypertrophy Induces O-linked-β-N-acetylglucosamine Modification of PGC-1α and Augments its Transcriptional Activity

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Heberty T Facundo ◽  
Charles R Pratridge ◽  
Sumanth D Prabhu ◽  
Steven P Jones
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Transcriptional Activation ◽  
Acid Metabolism ◽  
Mechanical Stretch ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels ◽  
Post Translational Modification ◽  
Rat Cardiomyocytes

Background and Hypothesis: PGC-1α (peroxisome proliferator activated receptor-gamma coactivator-1α) coordinately regulates fatty acid metabolism. The O-linked β-N-acetylglucosamine post-translational modification (O-GlcNAc) of proteins is a glucose-derived metabolic signal. We hypothesized that metabolic changes during cardiomyocyte hypertrophy might involve interaction between glycolysis and fatty acid metabolism, specifically via O-GlcNAc modification of PGC-1α. Methods and Results: Mechanical stretch (24 h at 4%; Flexercell FX-4000) in neonatal rat cardiomyocytes (n > 4/group) induced a significant (p<0.05) increase (113 ± 35% over No Stretch) in ANP mRNA, confirming induction of hypertrophy. Mechanical stretch significantly augmented (p<0.001; n = 5) global O-GlcNAcylation of several proteins, which was completely reversed by adenoviral overexpression of the deglycosylating enzyme (O-GlcNAcase). Mechanical stretch also augmented mRNA levels of O-GlcNAc transferase (OGT: adds O-GlcNAc to proteins) and glutamine:fructose aminotransferase (GFAT: rate-limiting step for the O-GlcNAc sugar donor), further indicating recruitment of O-GlcNAc signaling. Immunoprecipitation identified PGC-1α as an O-GlcNAc target in this cardiomyocyte hypertrophy model. Real-time (q)-PCR revealed that O-GlcNAc modification of PGC-1α correlated with elevated mRNA levels (n=4/group) of MCAD and COXIV-5b, implying transcriptional activation of PGC-1α. Conclusions: Cardiomyocyte hypertrophy induces O-GlcNAcylation of PGC-1α and represents a surprising and novel potential regulatory interaction between glycolytic and fatty acid metabolism. This research has received full or partial funding support from the American Heart Association, AHA National Center.

scholarly journals Anti-IL-17 Antibody Improves Hepatic Steatosis by Suppressing Interleukin-17-Related Fatty Acid Synthesis and Metabolism

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Weidong Shi ◽  
Qiang Zhu ◽  
Jian Gu ◽  
Xiaoshan Liu ◽  
Ling Lu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Hepatic Steatosis ◽  
Fatty Acid Metabolism ◽  
Alcoholic Liver Disease ◽  
Acid Metabolism ◽  
Binding Protein ◽  
Interleukin 17 ◽  
Expression Levels ◽  
Element Binding Protein

To investigate the relationship between interleukin-17 and proteins involved in fatty acid metabolism with respect to alcoholic liver disease, male ICR mice were randomized into five groups: control, alcoholic liver disease (ALD) at 4 weeks, 8 weeks, and 12 weeks, and anti-IL-17 antibody treated ALD. A proteomic approach was adopted to investigate changes in liver proteins between control and ALD groups. The proteomic analysis was performed by two-dimensional difference gel electrophoresis. Spots of interest were subsequently subjected to nanospray ionization tandem mass spectrometry (MS/MS) for protein identification. Additionally, expression levels of selected proteins were confirmed by western blot. Transcriptional levels of some selected proteins were determined by RT-PCR. Expression levels of 95 protein spots changed significantly (ratio >1.5,P<0.05) during the development of ALD. Sterol regulatory element-binding protein-lc (SREBP-1c), carbohydrate response element binding protein (ChREBP), enoyl-coenzyme A hydratase (ECHS1), and peroxisome proliferator-activated receptor alpha (PPAR-α) were identified by MS/MS among the proteins shown to vary the most; increased IL-17 elevated the transcription of SREBP-1c and ChREBP but suppressed ECHS1 and PPAR-α. The interleukin-17 signaling pathway is involved in ALD development; anti-IL-17 antibody improved hepatic steatosis by suppressing interleukin-17-related fatty acid metabolism.

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