Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice

Wu, Jing; Wang, Chunjiong; Li, Shuo; Li, Sha; Wang, Wanyi; Li, Jing; Chi, Yujing; Yang, Hang; Kong, Xiaomu; Zhou, Yunfeng; Dong, Chengyan; Fan, Wei; Xu, Guanghui; Yang, Jichun; Gustafsson, Jan‐Åke; Guan, Youfei

doi:10.1002/hep.26272

Cited by 75 publications

(74 citation statements)

References 38 publications

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“…THRSP should be highlighted as a special case as the gene array data could not be confirmed. THRSP expression was upregulated by many compounds, including VPA in Open TG-GATEs, and has previously been reported to play a role in the pathogenesis of liver steatosis (Wu et al 2013). However, induction of THRSP in cultivated human hepatocytes could not be confirmed after incubation with valproic acid, ketoconazole, and isoniazide (Table S8).…”

Section: In Vitro Reproduction Of Reported Compound-gene Effectsmentioning

confidence: 87%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically infl...

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Section: In Vitro Reproduction Of Reported Compound-gene Effectsmentioning

confidence: 87%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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“…As shown in ( Figure 1C), we successfully established the mouse model of NAFLD. 28 Figure 1D). These results suggest that lncRNA H19 expression may be associated with the development of hepatic steatosis.…”

Section: H19 Is Up-regulated In Oleic Acid-induced Steatosis and Dumentioning

confidence: 96%

“…The use and care of experimental animals was approved by the 27 The mouse model of NAFLD was established as previously described. 28 Briefly, 60 mice (C57BL/6, male, interpretation period) were obtained from and housed in the Experimental Animal Research Center at Chongqing Medical University. The mice were randomly divided into two groups, the high-fat diet (HFD) group and the control group (30 each).…”

Section: Establishment Of the Mouse Model Of Nonalcoholic Fatty LIVmentioning

confidence: 99%

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Wang

Cao

Shu

et al. 2019

J Cellular Molecular Medi

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Liver plays an essential role in regulating lipid metabolism, and chronically disturbed hepatic metabolism may cause obesity and metabolic syndrome, which may lead to non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates long noncoding RNAs (lncRNAs) play an important role in energy metabolism. Here, we investigated the role of lncRNA H19 in hepatic lipid metabolism and its potential association with NAFLD. We found that H19 was up-regulated in oleic acid-induced steatosis and during the development of high-fat diet (HFD)-induced NAFLD. Exogenous overexpression of H19 in hepatocytes induced lipid accumulation and up-regulated the expression of numerous genes involved in lipid synthesis, storage and breakdown, while silencing endogenous H19 led to a decreased lipid accumulation in hepatocytes. Mechanistically, H19 was shown to promote hepatic steatosis by up-regulating lipogenic transcription factor MLXIPL. Silencing Mlxipl diminished H19-induced lipid accumulation in hepatocytes. Furthermore, H19-induced lipid accumulation was effectively inhibited by PI3K/mTOR inhibitor PF-04691502. Accordingly, H19 overexpression in hepatocytes up-regulated most components of the mTORC1 signalling axis, which were inhibited by silencing endogenous H19. In vivo hepatocyte implantation studies further confirm that H19 promoted hepatic steatosis by up-regulating both mTORC1 signalling axis and MLXIPL transcriptional network. Collectively, these

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“…Of the 11 joint transcripts, 10 genes exhibited different patterns of expression, and only one gene that was coordinately regulated in both SM and RM diets (Figure 4c). This one coordinately regulated gene was thyroid hormone responsive spot 14 protein ( THRSP , also known as Spot 14 ), a transcription factor associated with de novo fatty acid synthesis in the liver 23. Interestingly, T329S induced a significant increase in THRSP expression that was more prominent under SM diets, suggesting that the genotype involved in regulating mechanisms through THRSP tend to become somewhat less efficient under the RM diets (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

Wang¹,

Lü²,

Zhang³

et al. 2016

Int. J. Biol. Sci.

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Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and diet factors. We used hens genotyped as FMO3 c.984 A>T as well as those with the homozygous normal genotype. For each genotype, hens were provided with either a corn-soybean meal basal diets (SM), which contains lower levels of TMA precursor, or the basal diets supplemented with 21% of rapeseed meal (RM), which contains higher levels of TMA precursor. An integrative analysis of metabolomic and transcriptomic was used to explore the metabolic patterns of FMO3 genetic variant in hens that were fed the two defined diets. In birds that consumed SM diets, the T329S mutation increased levels of plasma TMA and lipids, FMO3 mRNA levels, and the expression of genes involved in long chain polyunsaturated fatty acid biosynthesis. In birds that consumed RM diets, the T329S mutation induced fishy odor syndrome, a repression in LXR pathway and a reciprocal change in lipid metabolism. Variations in TMA and lipid metabolism were linked to the genetic variant in FMO3 in a diet-specific manner, which suggest FMO3 functions in TMA metabolism and lipid homeostasis. LXR pathway and polyunsaturated fatty acid metabolism are two possible mechanisms of FMO3 action in response to dietary TMA precursor.

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Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice

Cited by 75 publications

References 38 publications

Toxicogenomics directory of chemically exposed human hepatocytes

Toxicogenomics directory of chemically exposed human hepatocytes

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

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