Prenatal androgen exposure affects ovarian lipid metabolism and steroid biosynthesis in rats

Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldlr and Srb1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.

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

Circulation Research ◽

10.1161/res.119.suppl_1.3 ◽

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.

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Identification of differentially expressed genes and pathways between intramuscular and abdominal fat-derived preadipocyte differentiation of chickens in vitro

BMC Genomics ◽

10.1186/s12864-019-6116-0 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 8

Author(s):

Meng Zhang ◽

Fang Li ◽

Xiang-fei Ma ◽

Wen-ting Li ◽

Rui-rui Jiang ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Differentially Expressed Genes ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Adipogenic Differentiation ◽

Abdominal Fat ◽

Receptor Interaction ◽

Preadipocyte Differentiation ◽

Factors Affecting

Abstract Background The distribution and deposition of fat tissue in different parts of the body are the key factors affecting the carcass quality and meat flavour of chickens. Intramuscular fat (IMF) content is an important factor associated with meat quality, while abdominal fat (AbF) is regarded as one of the main factors affecting poultry slaughter efficiency. To investigate the differentially expressed genes (DEGs) and molecular regulatory mechanisms related to adipogenic differentiation between IMF- and AbF-derived preadipocytes, we analysed the mRNA expression profiles in preadipocytes (0d, Pre-) and adipocytes (10d, Ad-) from IMF and AbF of Gushi chickens. Results AbF-derived preadipocytes exhibited a higher adipogenic differentiation ability (96.4% + 0.6) than IMF-derived preadipocytes (86.0% + 0.4) (p < 0.01). By Ribo-Zero RNA sequencing, we obtained 4403 (2055 upregulated and 2348 downregulated) and 4693 (2797 upregulated and 1896 downregulated) DEGs between preadipocytes and adipocytes in the IMF and Ad groups, respectively. For IMF-derived preadipocyte differentiation, pathways related to the PPAR signalling pathway, ECM-receptor interaction and focal adhesion pathway were significantly enriched. For AbF-derived preadipocyte differentiation, the steroid biosynthesis pathways, calcium signaling pathway and ECM-receptor interaction pathway were significantly enriched. A large number of DEGs related to lipid metabolism, fatty acid metabolism and preadipocyte differentiation, such as PPARG, ACSBG2, FABP4, FASN, APOA1 and INSIG1, were identified in our study. Conclusion This study revealed large transcriptomic differences between IMF- and AbF-derived preadipocyte differentiation. A large number of DEGs and transcription factors that were closely related to fatty acid metabolism, lipid metabolism and preadipocyte differentiation were identified in the present study. Additionally, the microenvironment of IMF- and AbF-derived preadipocyte may play a significant role in adipogenic differentiation. This study provides valuable evidence to understand the molecular mechanisms underlying adipogenesis and fat deposition in chickens.

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Tomato seed oil attenuates hyperlipidemia and modulates gut microbiota in C57BL/6J mice

Food & Function ◽

10.1039/d0fo00133c ◽

2020 ◽

Vol 11 (5) ◽

pp. 4275-4290

Author(s):

Wen-Sen He ◽

Lingling Li ◽

Jiaxin Rui ◽

Junjie Li ◽

Yuying Sun ◽

...

Keyword(s):

Fatty Acid ◽

Gut Microbiota ◽

Fatty Acid Metabolism ◽

Seed Oil ◽

Acid Metabolism ◽

Cholesterol Metabolism ◽

Tomato Seed ◽

Tomato Seed Oil

TSO can significantly improve fatty acid metabolism and cholesterol metabolism, thereby inhibiting obesity and hypercholesterolemia. TSO can favorably modulate the gut microbiota.

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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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Lipid Metabolism Profiles in Rheumatic Diseases

Frontiers in Pharmacology ◽

10.3389/fphar.2021.643520 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weilin Chen ◽

Qi Wang ◽

Bin Zhou ◽

Lihua Zhang ◽

Honglin Zhu

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Rheumatic Diseases ◽

Fatty Acid Metabolism ◽

High Mortality ◽

Acid Metabolism ◽

Cell Metabolism ◽

Therapeutic Strategies ◽

Clinical Applications ◽

Multiple Organs

Rheumatic diseases are a group of chronic autoimmune disorders that involve multiple organs or systems and have high mortality. The mechanisms of these diseases are still ill-defined, and targeted therapeutic strategies are still challenging for physicians. Recent research indicates that cell metabolism plays important roles in the pathogenesis of rheumatic diseases. In this review, we mainly focus on lipid metabolism profiles (dyslipidaemia, fatty acid metabolism) and mechanisms in rheumatic diseases and discuss potential clinical applications based on lipid metabolism profiles.

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Multi-Omics Analysis of Fatty Acid Metabolism in Thyroid Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.737127 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinghui Lu ◽

Yankun Zhang ◽

Min Sun ◽

Changyuan Ding ◽

Lei Zhang ◽

...

Keyword(s):

Thyroid Cancer ◽

Fatty Acid ◽

Lipid Metabolism ◽

Thyroid Carcinoma ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Metabolic Reprogramming ◽

Clinical Samples ◽

Integrated Analysis ◽

Additional Energy

ObjectivePapillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.MethodsClinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.ResultsMulti-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.ConclusionsOur data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.

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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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Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cancers ◽

10.3390/cancers12092579 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2579

Author(s):

Diana Oelschlaegel ◽

Tommy Weiss Sadan ◽

Seth Salpeter ◽

Sebastian Krug ◽

Galia Blum ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Immune Cells ◽

Fatty Acid Synthase ◽

Acid Metabolism ◽

Metabolic Reprogramming ◽

Marker Genes ◽

Tumor Associated Macrophages ◽

Cathepsin Activity ◽

The Impact

Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

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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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