scholarly journals The Role of Histone Deacetylase 9 in the Therapeutic Effects of Astaxanthin on Non-Alcoholic Steatohepatitis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1257-1257
Author(s):  
Siqi Hu ◽  
Hyunju Kang ◽  
Hyungryun Jang ◽  
Minkyung Bae ◽  
Mi-Bo Kim ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Control Diet ◽  
Genotypic Differences ◽  
Therapeutic Effects ◽  
Inflammatory Genes ◽  
Female Mice ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Histone Deacetylase 9

Abstract Objectives The objectives of this study were to determine the role of histone deacetylase 9 (HDAC9) in the development of non-alcoholic steatohepatitis (NASH); and to evaluate the therapeutic effects of astaxanthin (ASTX), a xanthophyll carotenoid, on NASH via the modulation of HDAC9 in vivo. Methods Eight-week-old male and female wild-type (WT) and global Hdac9 knockout (KO) mice (n = 30/sex/genotype) were fed a high-fat/high-sucrose/high-cholesterol (HFHSHC) diet for 20 weeks to induce NASH. Subsequently, subsets of WT (n = 10/sex) and KO (n = 10/sex) mice were sacrificed to examine NASH features and served as baseline controls. The rest of the mice were randomly assigned into two diet groups for another 10 weeks: One continued on the HFHSHC diet, while the other group was fed an HFHSHC containing 0.03% ASTX (w/w). Results After 20 weeks on the HFHSHC diet, male KO mice had lower liver weights and triglycerides than WT, but no genotypic differences were observed in the female. Male KO mice showed less liver steatosis and fibrosis with significant decreases in the hepatic expression of lipogenic genes than male WT mice, but Hdac9 deletion did not inhibit NASH development in female mice. Compared with male KO baseline controls, consumption of control diet for an additional 10 week increased hepatic expression of lipogenic and pro-inflammatory genes in male KO mice, losing the beneficial effect of Hdac9 deletion shown at week 20 on the HFHSHC diet. However, the ASTX diet abrogated the induction. There were no significant differences in hepatic lipid contents and histological features of NASH between any genotypes regardless of ASTX supplementation. Also, additional control diet feeding did not induce any changes in hepatic gene expression in female mice, compared with those on the ASTX diet. Conclusions Hdac9 deletion protected male, but not female, mice from diet-induced hepatic steatosis and fibrosis, which may be attributable to decreased lipogenesis in the liver. However, the protection did not exist when liver damages progressed. Hdac9 deletion or ASTX alone did not alleviate the liver damage progression, but they together inhibited the induction of lipogenic and pro-inflammatory genes in the liver of male mice, indicating that they may have synergistic effects on ameliorating NASH progression. Funding Sources The study was supported by National Institutes of Health.

scholarly journals Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322509
Author(s):  
Eun Hee Koh ◽  
Ji Eun Yoon ◽  
Myoung Seok Ko ◽  
Jaechan Leem ◽  
Ji-Young Yun ◽  
...  
Keyword(s):  
Mouse Models ◽  
Free Cholesterol ◽  
High Cholesterol Diet ◽  
Inflammasome Activation ◽  
Hepatic Expression ◽  
Sphingomyelin Synthase ◽  
Alcoholic Steatohepatitis ◽  
Pyrin Domain ◽  
Hepatocyte Injury

ObjectiveLipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.DesignWild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).ResultsHFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.ConclusionSMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

scholarly journals Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

Adipocyte ◽  
2014 ◽  
Vol 3 (4) ◽  
pp. 333-338 ◽  
Author(s):  
Tapan K Chatterjee ◽  
Joshua E Basford ◽  
Kan Hui Yiew ◽  
David W Stepp ◽  
David Y Hui ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Histone Deacetylase ◽  
High Fat Diet ◽  
Adipogenic Differentiation ◽  
High Fat ◽  
Histone Deacetylase 9

scholarly journals Role of Fn14 in acute alcoholic steatohepatitis in mice

2015 ◽  
Vol 308 (4) ◽  
pp. G325-G334 ◽  
Author(s):  
Gamze Karaca ◽  
Guanhua Xie ◽  
Cynthia Moylan ◽  
Marzena Swiderska-Syn ◽  
Cynthia D. Guy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Injury ◽  
Control Diet ◽  
Alcohol Exposure ◽  
Tnf Receptor ◽  
High Fat ◽  
Alcoholic Steatohepatitis ◽  
Tnf Α ◽  
Induce Liver Injury

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14+ progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

scholarly journals POWERDRESS interacts with HISTONE DEACETYLASE 9 to promote aging in Arabidopsis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xiangsong Chen ◽  
Li Lu ◽  
Kevin S Mayer ◽  
Mark Scalf ◽  
Shuiming Qian ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Leaf Senescence ◽  
Underlying Mechanism ◽  
Nuclear Accumulation ◽  
Chromatin Binding ◽  
Genome Wide ◽  
Complex Process ◽  
Sant Domain ◽  
Histone Deacetylase 9

Leaf senescence is an essential part of the plant lifecycle during which nutrients are re-allocated to other tissues. The regulation of leaf senescence is a complex process. However, the underlying mechanism is poorly understood. Here, we uncovered a novel and the pivotal role of Arabidopsis HDA9 (a RPD3-like histone deacetylase) in promoting the onset of leaf senescence. We found that HDA9 acts in complex with a SANT domain-containing protein POWERDRESS (PWR) and transcription factor WRKY53. Our genome-wide profiling of HDA9 occupancy reveals that HDA9 directly binds to the promoters of key negative regulators of senescence and this association requires PWR. Furthermore, we found that PWR is important for HDA9 nuclear accumulation. This study reveals an uncharacterized epigenetic complex involved in leaf senescence and provides mechanistic insights into how a histone deacetylase along with a chromatin-binding protein contribute to a robust regulatory network to modulate the onset of plant aging.

scholarly journals Role of histone deacetylase 9 in the development of adipose tissue senescence

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Brandee Goo ◽  
Samah Ahmadieh ◽  
Abdalrahman Zarzour ◽  
Jacob Greenway ◽  
Mourad Ogbi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Histone Deacetylase ◽  
Histone Deacetylase 9

scholarly journals Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dániel Kucsera ◽  
Viktória E. Tóth ◽  
Dorottya Gergő ◽  
Imre Vörös ◽  
Zsófia Onódi ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Human Condition ◽  
Similar Degree ◽  
Middle Aged ◽  
Control Male ◽  
Male And Female ◽  
Female Mice ◽  
Aged Mice ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis

BackgroundThe prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.ObjectivesWe aimed to assess sex-specific differences in the expression of inflammatory and fibrotic genes, as well as in cholesterol metabolism, focusing on the expression of Pcsk9 in several tissues in a mouse model of NASH that shows the typical features of the human condition.Methods and ResultsWe fed 10-months-old male and female C57Bl/6J mice with a NASH-inducing CDAA or corresponding control diet for 8 weeks. We found that, compared to the control male mice baseline, hepatic Pcsk9 expression as well as serum PCSK9 level was significantly higher in females, and both circulating PCSK9 level and the hepatic Pcsk9 gene were markedly decreased in female mice during NASH development. Histological analysis revealed that male and female mice develop a similar degree of steatosis; however, fibrosis was more pronounced in males upon CDAA diet feeding. Strikingly, female mice have higher hepatic expression of the pro-inflammatory cytokines (Il1b, Ifng), and increased IL-1β cleavage by the NLRP3 inflammasome, and a decrease in Clec4f+ resident Kupffer cell population in comparison to males in the CDAA-fed groups.ConclusionThis is the first demonstration that there are critical sex-specific differences during NASH development in middle-aged mice regarding inflammation, fibrosis, and cholesterol metabolism and that changes in PCSK9 and IL-1β are likely important contributors to sex-specific changes during the transition to NASH.

scholarly journals Impact of Carotenoid Cleaving Enzymes on Lycopene Accumulation in Transgenic Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 69-69
Author(s):  
Joseph Arballo ◽  
Jaime Amengual ◽  
Molly Black ◽  
John Erdman
Keyword(s):  
High Performance ◽  
Statistical Significance ◽  
Control Diet ◽  
Knock Out ◽  
Female Mice ◽  
Funding Sources ◽  
Significance Threshold ◽  
Extrahepatic Tissues ◽  
Total Tissue

Abstract Objectives To evaluate the role of β-carotene oxygenase 1 (BCO1) and BCO2 on lycopene tissue distribution. Methods Three-week old C57BL/6 male and female mice (wild type [WT], Bco1−/−, Bco2−/−, Bco1−/− × Bco2−/− double knock out [DKO]) were divided into groups based on genotype (n = 16 per group split evenly by sex) and fed a powdered AIN 93G control diet for 2 weeks. After this period, mice were gavaged daily for 2 weeks with 1 mg of lycopene dissolved in cottonseed oil. 12 h-fasted mice were then sacrificed, and liver, serum, heart, kidney, intestine, gonadal adipose, prostate, spleen, and testes were harvested. Tissues were preserved in liquid nitrogen and stored at −80 until analyses. We measured lycopene levels in all samples by using high-performance liquid chromatography. Data analyses were performed using two-way ANOVA, followed by the Sidaks test with a statistical significance threshold of P < 0.05. Results Female mice showed higher lycopene levels in the intestine (P < 0.045) and liver (P < 0.007) irrespective of genotype, while male mice had higher lycopene levels in serum (P < 0.004). Intestine, serum, and kidneys exhibited higher lycopene levels in DKO mice compared to all other genotypes (P < .0001), while having higher lycopene levels in testes (P < 0.0001) compared to Bco2−/− and WT mice and adipose (P < 0.005) only in comparison to Bco2−/− mice. DKO exhibited higher lycopene levels in the spleen compared to Bco1−/− mice (P < 0.02). Lycopene levels in the liver (P < 0.0001) were higher in Bco2−/− mice compared to Bco1 −/− and DKO mice, while Bco1−/− mice had lower hepatic lycopene levels compared to all other genotypes. Conclusions Female mice accumulated higher lycopene levels in most tissues compared to males. These results were consistent when data were corrected by total tissue weight. The data suggest the absence of BCO2 favors carotenoid accumulation in many extrahepatic tissues, an effect that is enhanced in the absence of both carotenoid cleaving enzymes. Funding Sources Internal funding, University of Illinois Urbana Champaign.

scholarly journals Protective Role of Trans-chalcone against the Progression from Simple Steatosis to Non-alcoholic Steatohepatitis: Regulation of miR-122, 21, 34a, and 451

2021 ◽  
Author(s):  
Elham Karimi-Sales ◽  
Sajad Jeddi ◽  
Abbas Ebrahimi-Kalan ◽  
Mohammad Reza Alipour
Keyword(s):  
Tween 80 ◽  
Protective Role ◽  
Male Rats ◽  
Inflammatory Disorder ◽  
Expression Levels ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Aggressive Form ◽  
Induced Changes

Purpose: Non-alcoholic steatohepatitis (NASH) is an inflammatory disorder and an aggressive form of fatty liver disease. Certain microRNAs, including miR-122, 21, 34a, and 451, are involved in the transition from steatosis to NASH. This study examined how trans-chalcone (the core of chalcone derivatives) affects NAFLD progression by regulating miRNAs. Methods: Male rats were divided into three groups (n = 7/group) as follows: control, rats were gavaged with 10% tween 80 (for two weeks); NASH, rats were gavaged with a high-fat liquid diet (HFD; for six weeks) and 10% tween 80 (for two weeks); NASH + Chal, rats were gavaged with the HFD (for six weeks) and trans-chalcone (for two weeks). Hepatic expression levels of miR-122, 21, 34a, and 451 were determined. Results: trans-Chalcone reversed histological abnormalities, reduced liver injury markers, and attenuated insulin resistance in HFD-fed rats. In the liver, HFD-induced NASH increased the expression level of miR-34a and decreased expression levels of miR-122, 21, and 451. However, trans-chalcone inhibited HFD-induced changes in expression levels of these miRNAs. Conclusion: trans-Chalcone could inhibit the transition from steatosis to NASH through the modulation of miR-122, 21, 34a, and 451 expression levels in the liver.

Dual role of B7 costimulation in obesity-related non-alcoholic steatohepatitis (NASH) and metabolic dysregulation

2014 ◽  
Vol 122 (03) ◽  
Author(s):  
A Chatzigeorgiou ◽  
R Garcia-Martin ◽  
KJ Chung ◽  
I Alexaki ◽  
A Klotzsche-von Ameln ◽  
...  
Keyword(s):  
Dual Role ◽  
Alcoholic Steatohepatitis ◽  
Metabolic Dysregulation
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