Arylacetamide deacetylase: A novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production

Nourbakhsh, Mahra; Douglas, Donna N.; Pu, Christopher Hao; Lewis, Jamie; Kawahara, Toshiyasu; Lisboa, Luiz F.; Wei, Enhui; Asthana, Sonal; Quiroga, Ariel D.; Law, Lok Man J.; Chen, Chao; Addison, William R.; Nelson, Randal C.; Houghton, Michael; Lehner, Richard; Kneteman, Norman M.

doi:10.1016/j.jhep.2013.03.022

Cited by 30 publications

(30 citation statements)

References 19 publications

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“…In addition, nine of these 11 genes (except for AADAC and SLC25A42) have been reported to be direct PPAR target genes [11][12][13][14][15][16] . Arylacetamide deacetylase (AADAC) and SLC25A42 are involved in VLDL assembly 17) and coenzyme A transport 18) , respectively, and are important for determining the fatty acid fate. These results indicate that K-877 induces fatty acid catabolism in human hepatocytes.…”

Section: Quantitative Analysismentioning

confidence: 99%

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Raza-Iqbal

Tanaka

Anai

et al. 2015

J Atheroscler Thromb

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Aim: Selective PPAR modulators (SPPARM ) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARM K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. Methods: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARM on the liver gene expression. Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPAR with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid -oxidative genes in human hepatocytes and the mouse liver. Almost all genes up-or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly

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Section: Quantitative Analysismentioning

confidence: 99%

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Raza-Iqbal

Tanaka

Anai

et al. 2015

J Atheroscler Thromb

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“…Generation of Viral Stocks and Infected Cell Cultures-Viral stocks were collected from Huh7.5 cells transfected with Japanese fulminant hepatitis (JFH)-1 HCV RNA between 3 and 40 days post-transfection essentially as described (53,58). Infected cell cultures were generated by inoculating low passage Huh7.5 cells with viral stocks at a multiplicity of infection (m.o.i.)…”

Section: Methodsmentioning

confidence: 99%

“…Infected cell cultures were generated by inoculating low passage Huh7.5 cells with viral stocks at a multiplicity of infection (m.o.i.) ϭ 0.01 infectious virions/cell essentially as described (53,58). The percentage of HCV-infected cells and the production of viral RNA and infectivity titers were determined periodically by immunocytochemistry with anti-HCV core immunostaining, quantitative RT-PCR, and limiting dilution assays essentially as described (58,59).…”

Section: Methodsmentioning

confidence: 99%

“…Instead, these were enrolled into experiments as "infected" cells. "Naive" cells used in experiments were derived from the same Huh7.5 cell stocks as infected cells (58). Sequencing of the viral genome (Molecular Biology Services Unit, Dept.…”

Section: Methodsmentioning

confidence: 99%

“…After HCV infection, the percentage of HCV-infected cells and the production of viral RNA and infectious virions were determined periodically by immunocytochemistry with anti-HCV core immunostaining, quantitative RT-PCR, and limiting dilution assays essentially as described (58,59). Infected cell cultures were enrolled into experiments as "infected cells" at 10 days post-infection (m.o.i.…”

Section: Hcv-induced Cell Cycle Arrest Is Associated With Rosmentioning

confidence: 99%

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Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Douglas

Lewis

et al. 2016

Journal of Biological Chemistry

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Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and ␤-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor ␣, which plays a dominant role in the expression of ␤-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor ␣ is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced ␤-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced ␤-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.With ϳ200 million people infected worldwide, hepatitis C virus (HCV) 2 is a global health problem and a major cause of viral hepatitis. Persistent infection occurs in ϳ70% of infected patients leading to inflammation, insulin resistance, steatosis, fibrosis, and hepatocellular carcinoma (1). Current direct-acting antivirals are predicted to be a cure for most patients, but the high cost of this treatment means that the pathological consequences of persistent HCV infection will remain a concern.Although the pathology associated with chronic HCV infection was initially thought to be due to HCV-specific immune responses (2), the current opinion is that direct cytopathic effects in virally infected cells also contribute to HCV-associated liver injury (3, 4). The cellular mechanisms by which HCV replication might mediate liver injury are unclear, but there is no doubt that oxidative/nitrosative stress in HCV-infected cells plays an important role in the initiation and progression of liver damage (3, 5, 6). Oxidative/nitrosative stress essentially arises when the production of reactive oxygen (...

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Hepatic Lipid Droplets in Liver Function and Disease

et al. 2020

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Arylacetamide deacetylase: A novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production

Cited by 30 publications

References 19 publications

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Hepatic Lipid Droplets in Liver Function and Disease

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