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

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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FC 102PD INDUCED ARTERIOLAR AND PERITONEAL PATHOMECHANISMS ARE PARTIALLY REVERSED AFTER KIDNEY TRANSPLANTATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab135.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Conghui Zhang ◽

Maria Bartosova ◽

Betti Schaefer ◽

Rebecca Herzog ◽

Rimante Cerkauskiene ◽

...

Keyword(s):

Kidney Transplantation ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Acid Metabolism ◽

Parietal Peritoneum ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Cell Counts

Abstract Background and Aims Due to the unphysiological composition of PD fluids, chronic peritoneal dialysis (PD) induces progressive peritoneal fibrosis, hypervascularization, and vasculopathy. The evolution of the PD membrane and vasculopathy following kidney transplantation (KTx) is largely unknown. Method Arteriolar and peritoneal tissues were obtained from 107 children with chronic kidney disease (CKD5), 72 children on PD (treated with neutral pH PD fluids, with low glucose degradation product content, GDP) and 21 children, who underwent KTx 4-5 weeks after a median 21 months of PD. Specimen underwent standardized digital quantitative histomorphometry. Molecular mechanisms were studied in omental arterioles microdissected from surrounding fat by multi-omics followed by Gene Set Enrichment Analysis (GSEA); key findings were validated in parietal tissues of independent, matched cohorts by quantitative immunohistochemistry (n=15/group). Results Arteriolar transcriptome and proteome GSEA revealed suppression of leucocyte migration and T-cell activation / secretory pathways regulation, of sprouting angiogenesis biological processes and of epithelial proliferation and cell cycle after KTx as compared to PD. Lipid / fatty acid metabolism, autophagy and ATP synthesis pathways were activated. Transcriptome analysis including KTx, PD and CKD5 specifically attributed regulation of arteriolar lipid and fatty acid metabolism to transplantation and comprised 140 transcripts; their regulation was confirmed on the proteome level. Hub gene fatty acid synthase was identified by protein interaction analysis (string-db.org). 15 arteriolar genes activated by PD were inactivated after KTx and included glucose metabolisms and cytoskeleton related transcripts. 24 transcripts and 10 corresponding proteins induced by PD were still active after KTx and associated with biological processes related to TGF-ß signaling, fibrosis and mineral absorption. In line with arteriolar multi-omics findings, peritoneal hypervascularization induced by chronic PD was reversed after Tx to CKD5 level. CD45 positive tissue infiltrating leucocytes count was reduced by 40% and was independently associated with microvessel density in multivariable analysis including PD vintage, daily GDP exposure and recent KTx. Peritoneal lymphatic vessel density, submesothelial thickness, activated fibroblast, fibrin deposit, macrophage and EMT cell counts remained unchanged after KTx compared to PD. Arteriolar lumen to vessel ratios (a marker of vasculopathy) were similar in both groups. Vessel-homeostasis-related proteins in independent, matched cohorts demonstrated increased caspase-3 abundance in peritoneal arterioles after KTx. Arteriolar VEGF-A, thrombospondin, angiopoietin1/2, and hypoxia-inducible factor-1 (HIF-1a) were unchanged, while submesothelial HIF-1a and angiopoietin1/2 were decreased after Tx, favoring vessel maturation. The abundance of the key driver of fibrosis, TGF-ß-effector pSMAD2/3, was unchanged in the peritoneum and arterioles after Tx. Conclusion Our multi-omics analyses of fat covered omental arterioles, not directly exposed to PD fluids, demonstrate inhibition of PD induced immune response and angiogenesis pathways, of glucose metabolism and cytoskeleton regulation to levels similar as seen in children with CKD5. Arteriolar lipid and fatty acid metabolism is selectively altered after KTx. Reversal of low GDP PD induced hypervascularization and inflammation of the parietal peritoneum after KTx, mirror molecular changes in omental arterioles, while profibrotic activity persists after KTx in omental arterioles and in the parietal peritoneum.

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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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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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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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Effects of Plant Sterols Intake on Systematic and Tissue Specific Lipid Metabolism in C57BL/6J Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_098 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 388-388

Author(s):

Qian Zhu ◽

Jingjing Wu ◽

Daxue He ◽

Xuemei Lian

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Plant Sterols ◽

Differentially Expressed ◽

Rna Seq ◽

Tissue Specific ◽

Free Sterols ◽

Specific Lipid

Abstract Objectives To investigate the effects of plant sterols intake on systematic and tissue specific lipid metabolism in C57BL/6J mice. Methods Male C57BL/6J mice were randomly divided into control diet group (CS) and plant sterol group (PS, 2% plant sterols). After 28 weeks of continuous feeding, the serum of the mice were collected for biochemical and mass spectrometry tests. Serum levels of total cholesterol (TC), triglyceride (TG) and free sterols were determined. The livers and lungs were collected for free sterol quantification and RNA-seq analysis. Results Compared with the CS group, 2% plant sterols intake significantly reduced the levels of TC in the serum of mice (P < 0.05), with the TG level unchanged. The quantitative results of free sterols showed that the concentration of campesterol were increased, and the cholestanol levels were decreased significantly in the serum and liver of the PS group mice. The results of RNA-seq analysis were used to further evaluate its impact on the lipid metabolism related gene expression profile in the livers and lungs. The results showed that HMGCR, SQLE, HMGCS1, SREBF1, and other genes related to cholesterol synthesis in the PS group were significantly up-regulated in the liver, but not in the lung; Among the first 20 targeting pathways related to the action of plant sterols, the liver differentially expressed genes were enriched in lipid metabolism (steroid biosynthesis, terpenoid skeleton biosynthesis, peroxisome, bile acid secretion, PPAR, MAPK, fatty acid metabolism.), inflammation related (Cell adhesion molecules, leukocyte trans-endothelial migration) and amino acid metabolism (glutathione, valine, leucine and isoleucine metabolism). The differential genes in lung tissue are enriched in lipid metabolism (acetone metabolism, fatty acid metabolism, insulin resistance, terpenoid skeleton biosynthesis, iron death, PPAR), cell function (internal Swallowing, aging) and vascular smooth muscle contraction etc. Conclusions Differentially expressed gene networks reflect the multi-dimensional regulation of plant sterols on tissue specific lipid metabolism, which lays a good foundation for further revealing its mechanism. Funding Sources Yihaikerry Nutrition and Food Safety Foundation, Chinese Nutrition Society; Project of Technology Innovation and Application, Chongqing, China

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Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance

ISRN Hepatology ◽

10.1155/2013/534972 ◽

2013 ◽

Vol 2013 ◽

pp. 1-21 ◽

Cited By ~ 8

Author(s):

Guoxun Chen

Keyword(s):

Insulin Resistance ◽

Transcription Factors ◽

Retinoic Acid ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Hepatic Insulin Resistance ◽

Glucose And Lipid Metabolism ◽

Hepatic Genes

The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells.

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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

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RiboTag translatomic profiling of Drosophila oenocytes under aging and oxidative stress

10.1101/272179 ◽

2018 ◽

Author(s):

Kerui Huang ◽

Wenhao Chen ◽

Fang Zhu ◽

Hua Bai

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Lipid Metabolism ◽

Stress Response ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Fat Body ◽

Mapk Signaling ◽

Age Related ◽

And Oxidative Stress

AbstractBackgroundAging is accompanied with loss of tissue homeostasis and accumulation of cellular damages. As one of the important metabolic centers, aged liver shows altered lipid metabolism, impaired detoxification pathway, increased inflammation and oxidative stress response. However, the mechanisms for these age-related changes still remain unclear. In fruit flies, Drosophila melanogaster, liver-like functions are controlled by two distinct tissues, fat body and oenocytes. Although the role of fat body in aging regulation has been well studied, little is known about how oenocytes age and what are their roles in aging regulation. To address these questions, we used cell-type-specific ribosome profiling (RiboTag) to study the impacts of aging and oxidative stress on oenocyte translatome in Drosophila.ResultsWe show that aging and oxidant paraquat significantly increased the levels of reactive oxygen species (ROS) in adult oenocytes of Drosophila, and aged oenocytes exhibited reduced sensitivity to paraquat treatment. Through RiboTag sequencing, we identified 3324 and 949 differentially expressed genes in oenocytes under aging and paraquat treatment, respectively. Aging and paraquat exhibit both shared and distinct regulations on oenocyte translatome. Among all age-regulated genes, mitochondrial, proteasome, peroxisome, fatty acid metabolism, and cytochrome P450 pathways were down-regulated, whereas DNA replication and glutathione metabolic pathways were up-regulated. Interestingly, most of the peroxisomal genes were down-regulated in aged oenocytes, including peroxisomal biogenesis factors and beta-oxidation genes. Further analysis of the oenocyte translatome showed that oenocytes highly expressed genes involving in liver-like processes (e.g., ketogenesis). Many age-related transcriptional changes in oenocytes are similar to aging liver, including up-regulation of Ras/MAPK signaling pathway and down-regulation of peroxisome and fatty acid metabolism.ConclusionsOur oenocyte-specific translatome analysis identified many genes and pathways that are shared between Drosophila oenocytes and mammalian liver, highlighting the molecular and functional similarities between the two tissues. Many of these genes are altered in both aged oenocytes and aged liver, suggesting a conserved molecular mechanism underlying oenocyte and liver aging. Thus, our translatome analysis will contribute significantly to the understanding of oenocyte biology, and its role in lipid metabolism, stress response and aging regulation.

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