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Gholamreza Bidkhori, Rui Benfeitas, Martina Klevstig, Cheng Zhang, Jens Nielsen, Mathias Uhlen, Jan Boren, Adil Mardinoglu
Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels...
December 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Chen Huang, Bin-Bin Huang, Jian-Min Niu, Yan Yu, Xiao-Yun Qin, Ya-Li Yang, Tian-Xia Xiao, Jie Chen, Li-Rong Ren, Jian V Zhang
BACKGROUND/AIMS: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, but the mechanisms underlying the disorders remain unclear. The study aimed to identify mRNA and long non-coding RNA (lncRNA) profiles in placenta and gonadal fat of pregnant mice fed a high-fat diet and to investigate the transcripts and pathways involved in the development of gestational diabetes mellitus. METHODS: Deep and broad transcriptome profiling was performed to assess the expression of mRNAs and lncRNAs in placenta and gonadal fat from 3 mice fed an HFD and chow during pregnancy...
2018: Cellular Physiology and Biochemistry
Vinicius Tragante, Daiane Hemerich, Mohammad Alshabeeb, Ingrid Brænne, Harri Lempiäinen, Riyaz S Patel, Hester M den Ruijter, Michael R Barnes, Jason H Moore, Heribert Schunkert, Jeanette Erdmann, Folkert W Asselbergs
BACKGROUND: Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS: We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs...
August 2018: Circulation. Genomic and precision medicine
Tao Wang, Honggu Lee, Yuguo Zhen
Cis-9-conjugated, trans-11-conjugated linoleic acid (CLA) is known for its positive activities on human health. The synthesis of cis-9, trans-11 CLA in mammary glands is generally thought to be catalyzed by stearoyl-CoA desaturase 1 (SCD1), but this has not been rigorously established. In this study, we hypothesized that the inhibition of SCD1 (by CAY10566) would block the synthesis of cis-9, trans-11 CLA in bovine mammary alveolar cells (MAC-T) cells. Results showed that MAC-T cells incubated with 10 nM CAY10566 for 12 h (CAY) produced less cis-9, trans-11 CLA (p < 0...
June 2018: Lipids
Zhiguang Huang, Menglu Zhang, Abigail A Plec, Sandi Jo Estill, Ling Cai, Joyce J Repa, Steven L McKnight, Benjamin P Tu
Acetyl-CoA synthetase 2 (ACSS2) is a conserved nucleocytosolic enzyme that converts acetate to acetyl-CoA. Adult mice lacking ACSS2 appear phenotypically normal but exhibit reduced tumor burdens in mouse models of liver cancer. The normal physiological functions of this alternate pathway of acetyl-CoA synthesis remain unclear, however. Here, we reveal that mice lacking ACSS2 exhibit a significant reduction in body weight and hepatic steatosis in a diet-induced obesity model. ACSS2 deficiency reduces dietary lipid absorption by the intestine and also perturbs repartitioning and utilization of triglycerides from adipose tissue to the liver due to lowered expression of lipid transporters and fatty acid oxidation genes...
October 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Gong-Hao He, Jia-Qi Ding, Xin Zhang, Wen-Mang Xu, Xiao-Qian Lin, Mei-Jin Huang, Ju Feng, Ping Wang, Wen-Ke Cai
Although dysregulation of histamine H4 receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients...
September 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
He Wen, Sujin Lee, Wei-Guo Zhu, Ok-Jun Lee, Seok Joong Yun, Jayoung Kim, Sunghyouk Park
Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and resistant (T24R) bladder cancer cells. Real-time live metabolomics revealed that T24R cells consume more glucose, leading to higher production of glucose-derived acetate and fatty acids. Along with the activation of general metabolic regulators, enzymes involved in acetate usage (ACSS2) and fatty acid synthesis (ACC) and a precursor for fatty acid synthesis (acetyl-CoA) were elevated in T24R cells...
June 5, 2018: Biochimica et biophysica acta. Molecular and cell biology of lipids
Huifen Xu, Jun Luo, Huibin Tian, Jun Li, Xueying Zhang, Zhi Chen, Ming Li, Juan J Loor
In mammals, sterol regulatory element binding protein-1 (SREBP-1) is the master regulator of fatty acid and triacylglycerol synthesis. Recent gene silencing studies in mammary cells indicate that SREBP-1 has a central role in milk fat synthesis. However, SREBP-1 knockdown studies in goat mammary cells have not been performed; hence, its direct role in controlling mRNA expression of lipid metabolism genes and triacylglycerol synthesis remains unknown. Inhibition of SREBP-1 in goat mammary epithelial cells (GMEC) by small interference RNA (siRNA) markedly reduced the content of cellular triacylglycerol (~50% decrease, P < 0...
June 4, 2018: Journal of Animal Science
Min Young Lee, Austin Yeon, Muhammad Shahid, Eunho Cho, Vikram Sairam, Robert Figlin, Khae-Hwan Kim, Jayoung Kim
Due to its tendency to recur and acquire chemoresistance quickly, bladder cancer (BC) remains to be an elusive and difficult disease. Patients with recurrent and chemoresistant BC have an extremely poor prognosis. One possible approach that may provide insightful and valuable information regarding resistance mechanisms is looking into the lipid metabolism of BC cells. Metabolism of lipids is essential for cancer cells and is associated with the regulation of a variety of key cellular processes and functions...
March 2, 2018: Oncotarget
Shaojin Zhang, Juanjuan He, Zhankui Jia, Zechen Yan, Jinjian Yang
BACKGROUND: Acetyl-CoA synthetase 2 (ACSS2) is highly expressed in various cancers, whereas ACSS2 expression and function in renal cell carcinoma (RCC) are unknown. METHODS: We investigated ACSS2 expression in 198 human RCC tissues using immunohistochemistry, and analyzed its clinicopathological correlation and prognostic relevance. Overexpression and knockdown of ACSS2 were used to investigate the proliferation, migration and invasion of human RCC 786-O, 769-P, and ACHN cell lines...
May 2018: Urologic Oncology
Guochun Jiang, Don Nguyen, Nancie M Archin, Steven A Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M Elsheikh, George R Thompson, Dennis J Hartigan-O'Connor, David M Margolis, Joseph K Wong, Satya Dandekar
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2)...
March 1, 2018: Journal of Clinical Investigation
Lv Yao, Xiaoqiang Guo, Yaoting Gui
BACKGROUND/AIMS: Reprogramming energy metabolism is an emerging hallmark of many cancers, and this alteration is especially evident in renal cell carcinomas (RCCs). However, few studies have been conducted on lipid metabolism. This study investigated the function and mechanism of lipid metabolism-related acetyl-CoA synthetase 2 (ACSS2) in RCC development, cell migration and invasion. METHODS: Quantitative real-time PCR (qRT-PCR) was used to determine the expression of ACSS2 in cancer tissue and adjacent tissue...
2018: Cellular Physiology and Biochemistry
Tim Martin Knutsen, Hanne Gro Olsen, Valeria Tafintseva, Morten Svendsen, Achim Kohler, Matthew Peter Kent, Sigbjørn Lien
The relative abundance of specific fatty acids in milk can be important for consumer health and manufacturing properties of dairy products. Understanding of genes controlling milk fat synthesis may contribute to the development of dairy products with high quality and nutritional value. This study aims to identify key genes and genetic variants affecting de novo synthesis of the short- and medium-chained fatty acids C4:0 to C14:0. A genome-wide association study using 609,361 SNP markers and 1,811 animals was performed to detect genomic regions affecting fatty acid levels...
February 1, 2018: Scientific Reports
Wentong Li, Yalan Yang, Ying Liu, Shuai Liu, Xiuxiu Li, Yingping Wang, Yanmin Zhang, Hui Tang, Rong Zhou, Kui Li
Fat deposition is an important economic trait in farm animals as well as obesity related diseases in humans, and the liver is a central organ involved in regulating lipid synthesis and metabolism in mammals. In this study, the pig liver transcriptome of two groups (H and L) showing differences in backfat thickness were profiled using RNA-Seq and miRNA-Seq to further explore the molecular mechanism of fat deposition. A total of 238 differentially expressed genes (DEGs) and 58 differentially expressed miRNAs were identified between the H and L group...
December 29, 2017: Oncotarget
Rui Chen, Min Xu, Jason Nagati, Joseph A Garcia
Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus...
2017: PloS One
Bhaskar Ganguly, Tanuj Kumar Ambwani, Sunil Kumar Rastogi
Milk fat is one of the most important economic traits in dairy animals. Yet, the biological machinery involved in milk fat synthesis remains poorly understood. In the present study, expression profiling of 45 genes involved in lipid biosynthesis and secretion was performed using a computational approach to identify those genes that are differentially expressed in mammary tissue. Transcript abundance was observed for genes associated with nine bioprocesses, namely, fatty acid import into cells, xenobiotic and cholesterol transport, acetate and fatty acid activation and intracellular transport, fatty acid synthesis and desaturation, triacylglycerol synthesis, sphingolipid synthesis, lipid droplet formation, ketone body utilization, and regulation of transcription in mammary, skin, and muscle tissue...
2017: Genetics Research International
Joan Sanchez-Gurmaches, Yuefeng Tang, Naja Zenius Jespersen, Martina Wallace, Camila Martinez Calejman, Sharvari Gujja, Huawei Li, Yvonne J K Edwards, Christian Wolfrum, Christian M Metallo, Søren Nielsen, Camilla Scheele, David A Guertin
Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild-cold-adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic β-oxidative capacity, we find paradoxically that the anabolic de novo lipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold and that, in humans, DNL correlates with Ucp1 expression...
January 9, 2018: Cell Metabolism
Tong Yu, Long Cui, Chenying Liu, Guanghui Wang, Tingyu Wu, Yuji Huang
OBJECTIVE: To investigate the expression of acetyl coenzyme A synthetase short-chain family member 2 (ACSS2) in patients with colorectal cancer (CRC) and its biological role. METHODS: A total of 74 CRC tissue samples and 40 normal colorectal tissues were tested by immunohistochemical staining to detect the expression of ACSS2 (cell staining intensity score: 0 points: without staining, 1 points: weak staining, 2 points: intensity staining, 3 point: strong staining; the percentage of positive cells in tumor or negative score: 0 points: negative, 1 point: <25% positive cells, 2 points: 25%-50% positive cells, 3 points: 50%-75% positive cells, 4 points: >75% positive cells...
October 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
Jung Nam Lee, Yong Wang, Ya Ou Xu, Yu Can Li, Fang Tian, Ming Feng Jiang
This research communication describes the profile of gene expression related to the synthesis of yak milk as determined via quantitative reverse transcription polymerase chain reaction (RT-qPCR). Significant up-regulation during lactation were observed in genes related to fatty acid (FA) uptake from blood (LPL, CD36), intracellular FA transport (FABP3), intracellular FA activation of long- and short-chain FAs (ACSS1, ACSS2, ACSL1), de novo synthesis (ACACA), desaturation (SCD), triacyglycerol (TAG) synthesis (AGPAT6, GPAM, LPIN1), lipid droplet formation (PLIN2, BTN1A1, XDH), ketone body utilisation (BDH1, OXCT1), and transcription regulation (THRSP, PPARGC1A)...
August 2017: Journal of Dairy Research
Xinjian Li, Xu Qian, Zhimin Lu
Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritional stress induces nuclear translocation of ACSS2 (acyl-CoA synthetase short-chain family member 2). This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding...
October 3, 2017: Autophagy
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