Effect of Guggulsterone on the Expression of Adiponectin in 3T3-L1 Cells

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.

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ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

10.2337/figshare.13102934.v1 ◽

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 in vivo and in vitro. 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.

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Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs

Communications Biology ◽

10.1038/s42003-020-01348-8 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Hongyan Ren ◽

Wei Xiao ◽

Xingliang Qin ◽

Gangzhi Cai ◽

Hao Chen ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Muscle Growth ◽

Subcutaneous Fat ◽

Fat Deposition ◽

Wild Type ◽

Binding Prediction ◽

Stearoyl Coa Desaturase

Abstract Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.

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

Endocrinology ◽

10.1210/en.2004-0877 ◽

2004 ◽

Vol 145 (12) ◽

pp. 5493-5503 ◽

Cited By ~ 31

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.

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Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer

Nature Communications ◽

10.1038/s41467-021-24656-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Li-Yan Li ◽

Qian Yang ◽

Yan-Yi Jiang ◽

Wei Yang ◽

Yuan Jiang ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Human Cancer ◽

Regulatory Element ◽

Regulatory Elements ◽

Gene Set Enrichment Analysis ◽

Transcriptional Dysregulation

AbstractSquamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.1.r183 ◽

2001 ◽

Vol 280 (1) ◽

pp. R183-R190 ◽

Cited By ~ 77

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.

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

Circulation ◽

10.1161/circ.118.suppl_18.s_331 ◽

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.

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CHANGES IN mRNA LEVELS OF INTRACELLULAR FATTY ACID METABOLISM REGULATORS IN HUMAN HEPATOMA HepG2 CELLS FOLLOWING THEIR TREATMENT WITH NON-ESTERIFIED FATTY ACIDS AND DEHYDROEPIANDROSTERONE

Biomedical Papers ◽

10.5507/bp.2005.034 ◽

2005 ◽

Vol 149 (2) ◽

pp. 251-256 ◽

Cited By ~ 4

Author(s):

Miroslav Rypka ◽

Katerina Cervenkova ◽

Lenka Uherkova ◽

Hana Poczatkova ◽

Katerina Bogdanova ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Hepg2 Cells ◽

Acid Metabolism ◽

Mrna Levels ◽

Human Hepatoma ◽

Esterified Fatty Acids ◽

Human Hepatoma Hepg2 Cells ◽

Hepatoma Hepg2

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ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

10.2337/figshare.13102934 ◽

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 in vivo and in vitro. 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.

Download Full-text