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Wang F, Wang X, Odle J, Maltecca C, Lin X. Maternal Supplementation of Dietary Choline and DHA During Gestational Nutrition Restriction Alters Hepatic mRNA and miRNA Expression Patterns in Full-Term Fetal Pigs. J Nutr 2025; 155:804-816. [PMID: 39805404 DOI: 10.1016/j.tjnut.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Supplementing choline and DHA to pregnant gilts modified fetal pig hepatic global DNA methylation induced by gestational malnutrition, suggesting that gene expression and regulation and its associated metabolic pathways are affected in the liver of offspring during growth and development. OBJECTIVES This study aimed to investigate the effect of maternal supplementation of choline, DHA, and their interaction on hepatic mRNA expression, miRNA regulation, and metabolic pathways in the fetal pigs born to malnourished mothers. METHODS The abundance of mRNA and miRNA was profiled in fetal liver from sows with undernutrition supplemented with choline and DHA in a 2 × 2 factorial design. The effects of choline, DHA, and their interaction on mRNA and miRNA expression were evaluated. Identification of the Biological Processes from the Gene Ontology database and miRNA Target Prediction Analysis were performed using the DAVID Functional Annotation Tool and Ingenuity Pathway Analysis. The identified miRNA-mRNA pairings were validated using RT-qPCR. RESULTS In total, 144 mRNA and 1 miRNA were altered by supplementation of choline, and the alterations were associated with the inhibitions of cardiac hypertrophy signaling, IL-6 signaling, IL-3 signaling, the Th1 pathway, and the acute phase response signaling pathway. Further, 151 mRNAs and 6 miRNAs were altered by maternal supplementation DHA and were associated with inhibition of 5 inositol-related pathways, 5 immune-related pathways, and 7 other pathways and the stimulation of peroxisome proliferator-activated receptor signaling and RhoGDI signaling pathways. In addition, 383 mRNAs and 25 miRNAs displayed choline × DHA interactions including synergistic effects on acute phase response signaling, and antagonistic effects on tRNA splicing, peroxisome proliferator-activated receptor α/retinoid X receptor α activation, and sirtuin signaling, NAD signaling, and RNA polymerase I transcription pathways. Ten of the identified 20 miRNA-mRNA pairings were validated using RT-qPCR. CONCLUSIONS The supplementation of choline, DHA, or choline plus DHA to pregnant gilts modifies liver mRNA, miRNA, and pathways in fetal pigs during gestational undernutrition.
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Affiliation(s)
- Feng Wang
- Department of Animal Sciences, North Carolina State University, Raleigh, NC, United States
| | - Xiaoqiu Wang
- Department of Animal Sciences, North Carolina State University, Raleigh, NC, United States
| | - Jack Odle
- Department of Animal Sciences, North Carolina State University, Raleigh, NC, United States
| | - Christian Maltecca
- Department of Animal Sciences, North Carolina State University, Raleigh, NC, United States
| | - Xi Lin
- Department of Animal Sciences, North Carolina State University, Raleigh, NC, United States.
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Jung JW, Wang F, Turk A, Park JS, Ma H, Ma Y, Noh HR, Sui G, Shin DS, Lee MK, Roh YS. Zaluzanin C Alleviates Inflammation and Lipid Accumulation in Kupffer Cells and Hepatocytes by Regulating Mitochondrial ROS. Molecules 2023; 28:7484. [PMID: 38005205 PMCID: PMC10672841 DOI: 10.3390/molecules28227484] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/02/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Zaluzanin C (ZC), a sesquiterpene lactone isolated from Laurus nobilis L., has been reported to have anti-inflammatory and antioxidant effects. However, the mechanistic role of ZC in its protective effects in Kupffer cells and hepatocytes has not been elucidated. The purpose of this study was to elucidate the efficacy and mechanism of action of ZC in Kupffer cells and hepatocytes. ZC inhibited LPS-induced mitochondrial ROS (mtROS) production and subsequent mtROS-mediated NF-κB activity in Kupffer cells (KCs). ZC reduced mRNA levels of pro-inflammatory cytokines (Il1b and Tnfa) and chemokines (Ccl2, Ccl3, Ccl4, Cxcl2 and Cxcl9). Tumor necrosis factor (TNF)-α-induced hepatocyte mtROS production was inhibited by ZC. ZC was effective in alleviating mtROS-mediated mitochondrial dysfunction. ZC enhanced mitophagy and increased mRNA levels of fatty acid oxidation genes (Pparα, Cpt1, Acadm and Hadha) and mitochondrial biosynthetic factors (Pgc1α, Tfam, Nrf1 and Nrf2) in hepatocytes. ZC has proven its anti-lipid effect by improving lipid accumulation in hepatocytes by enhancing mitochondrial function to facilitate lipid metabolism. Therefore, our study suggests that ZC may be an effective compound for hepatoprotection by suppressing inflammation and lipid accumulation through regulating mtROS.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Mi-Kyeong Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea; (J.-W.J.); (F.W.); (A.T.); (J.-S.P.); (H.M.); (Y.M.); (H.-R.N.); (G.S.); (D.-S.S.)
| | - Yoon Seok Roh
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea; (J.-W.J.); (F.W.); (A.T.); (J.-S.P.); (H.M.); (Y.M.); (H.-R.N.); (G.S.); (D.-S.S.)
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Liu T, Wang Q, Zhou L, Zhang P, Mi L, Qiu X, Chen Z, Kuang H, Li S, Lin JD. Intrahepatic paracrine signaling by cardiotrophin-like cytokine factor 1 ameliorates diet-induced NASH in mice. Hepatology 2023; 78:1478-1491. [PMID: 35950514 PMCID: PMC9918604 DOI: 10.1002/hep.32719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease-associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. APPROACH AND RESULTS Here, we performed transcriptomic analyses and identified cardiotrophin-like cytokine factor 1 (CLCF1), a member of the IL-6 family cytokines, as a cholangiocyte-derived paracrine factor that was elevated in the liver from diet-induced NASH mice and patients with NASH. Adenovirus-associated virus-mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet-induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte-specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. CONCLUSIONS Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.
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Affiliation(s)
- Tongyu Liu
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Qiuyu Wang
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Linkang Zhou
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Peng Zhang
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Lin Mi
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Xiaoxue Qiu
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Zhimin Chen
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Henry Kuang
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Siming Li
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Jiandie D. Lin
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
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Nimphy J, Ibrahim S, Dayoub R, Kubitza M, Melter M, Weiss TS. Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun. Int J Mol Sci 2023; 24:ijms24098107. [PMID: 37175814 PMCID: PMC10179097 DOI: 10.3390/ijms24098107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.
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Affiliation(s)
- Jonas Nimphy
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Sara Ibrahim
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Rania Dayoub
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Marion Kubitza
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Melter
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Thomas S Weiss
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
- Center for Liver Cell Research, University Hospital Regensburg, 93053 Regensburg, Germany
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Li Y, Zhou X, Dou Z, Deng D, Bing D. Clinical features and prognosis of pediatric idiopathic sudden sensorineural hearing loss: A bi-center retrospective study. Front Neurol 2023; 14:1121656. [PMID: 37006497 PMCID: PMC10050692 DOI: 10.3389/fneur.2023.1121656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/20/2023] [Indexed: 03/17/2023] Open
Abstract
ObjectiveLimited research has focused on the clinical features of sudden sensorineural hearing loss (SSNHL) in pediatric patients. This study is aimed to investigate the relationship between clinical features and the baseline hearing severity and outcomes of SSNHL in the pediatric population.MethodWe conducted a bi-center retrospective observational study in 145 SSNHL patients aged no more than 18 years who were recruited between November 2013 and October 2022. Data extracted from medical records, audiograms, complete blood count (CBC) and coagulation tests have been assessed for the relationship with the severity (the thresholds of the initial hearing) and outcomes (recovery rate, hearing gain and the thresholds of the final hearing).ResultsA lower lymphocyte count (P = 0.004) and a higher platelet-to-lymphocyte ratio (PLR) (P = 0.041) were found in the patient group with profound initial hearing than in the less severe group. Vertigo (β = 13.932, 95%CI: 4.082–23.782, P = 0.007) and lymphocyte count (β = −6.686, 95%CI: −10.919 to −2.454, P = 0.003) showed significant associations with the threshold of the initial hearing. In the multivariate logistic model, the probability of recovery was higher for patients with ascending and flat audiograms compared to those with descending audiograms (ascending: OR 8.168, 95% CI 1.450–70.143, P = 0.029; flat: OR 3.966, 95% CI 1.341–12.651, P = 0.015). Patients with tinnitus had a 3.2-fold increase in the probability of recovery (OR 3.222, 95% CI 1.241–8.907, P = 0.019), while the baseline hearing threshold (OR 0.968, 95% CI 0.936–0.998, P = 0.047) and duration to the onset of therapy (OR 0.942, 95% CI 0.890–0.977, P = 0.010) were negatively associated with the odds of recovery.ConclusionsThe present study showed that accompanying tinnitus, the severity of initial hearing loss, the time elapse and the audiogram configuration might be related to the prognosis of pediatric SSNHL. Meanwhile, the presence of vertigo, lower lymphocytes and higher PLR were associated with worse severity.
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Affiliation(s)
- Yingqiang Li
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaowei Zhou
- Otological Department, The First People's Hospital of Foshan, Foshan, China
| | - Zhiyong Dou
- School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, China
| | - Dongzhou Deng
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Bing
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Dan Bing
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Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
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Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
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Knecht S, Eberl HC, Bantscheff M. Interval-Based Secretomics Unravels Acute-Phase Response in Hepatocyte Model Systems. Mol Cell Proteomics 2022; 21:100241. [PMID: 35525403 PMCID: PMC9184749 DOI: 10.1016/j.mcpro.2022.100241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 11/21/2022] Open
Abstract
Mass spectrometry-based secretomics approaches frequently utilize serum-free culture conditions to circumvent serum-induced interference and to increase analytical depth. However, this can negatively affect a wide range of cellular functions and cell viability. These effects become particularly apparent when investigating transcriptionally regulated secretion events and feedback-loops in response to perturbations that require 48 h or more to fully manifest. We present an “interval-based” secretomics workflow, which determines protein secretion rates in short serum-free time windows. Relative quantification using tandem mass tags enables precise monitoring of time-dependent changes. We applied this approach to determine temporal profiles of protein secretion in the hepatocyte model cell lines HepG2 and HepaRG after stimulation of the acute-phase response (APR) by the cytokines IL1b and IL6. While the popular hepatocarcinoma cell line HepG2 showed an incomplete APR, secretion patterns derived from differentiated HepaRG cells recapitulated the expected APR more comprehensively. For several APR response proteins, substantial secretion was only observed after 72 h, a time window at which cell fitness is substantially impaired under serum-free cell culture conditions. The interval-based secretomics approach enabled the first comprehensive analysis of time-dependent secretion of liver cell models in response to these proinflammatory cytokines. The extended time range facilitated the observation of distinct chronological phases and cytokine-dependent secretion phenotypes of the APR. IL1b directed the APR toward pathogen defense over three distinct phases—chemotaxis, effector, clearance—while IL6 directed the APR toward regeneration. Protein shedding on the cell surface was pronounced upon IL1b stimulation, and small molecule inhibition of ADAM and matrix metalloproteases identified induced as well as constitutive shedding events. Inhibition of ADAM proteases with TAPI-0 resulted in reduced shedding of the sorting receptor SORT1, and an attenuated cytokine response suggesting a direct link between cell surface shedding and cytokine secretion rates.
Interval-based secretomics enables extended time course analysis. Time-resolved acute phase response in liver model systems HepG2 and HepaRG. IL1b response clusters in three phases. Cell surface shedding is amplified during acute-phase response. ADAM inhibition dampens secretion of inflammatory cytokines.
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Affiliation(s)
- Sascha Knecht
- Cellzome GmbH, GlaxoSmithKline (GSK), Heidelberg, Germany
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Zhu F, Zhang D, Shen F, Xu K, Huang X, Liu J, Zhang J, Teng Y. Maternal Socs3 knockdown attenuates postnatal obesity caused by an early life environment of maternal obesity and intrauterine overnutrition in progeny mice. IUBMB Life 2021; 73:1210-1221. [PMID: 34184397 DOI: 10.1002/iub.2526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 03/29/2021] [Accepted: 06/20/2021] [Indexed: 11/07/2022]
Abstract
Pathological states in the early life environment of mammalian offspring, including maternal obesity and intrauterine overnutrition, can induce obesity and metabolic disorder later in life. Leptin resistance caused by upregulation of Socs3 in the hypothalamus of offspring was believed to be the main mechanism of this effect. In this study, obese mother (OM) and lean mother (LM) models were generated by feeding C57BL/6N female mice a high-fat diet or standard lean diet, respectively. Additionally, an obese mother with intervention (OMI) model was generated by injecting the high-fat diet group with Socs3-shRNA lentivirus during early pregnancy. The offspring of the groups was correspondingly named OM-F1 , LM-F1 , and OMI-F1 , representing progeny mouse models of different early life environments. The offspring were fed a high-fat diet to test their propensity for obesity. The body weight, food intake and fat accumulation were higher, while glucose intolerance and insulin resistance were worse in the OM-F1 group than LM-F1 group. By contrast, the obesity phenotype, hyperphagia and metabolic disorder were alleviated in the OMI-F1 group compared with the OM-F1 group. The mechanism was identified that downregulation of hypothalamic SOCS3 resulted in an increased level of p-STAT3 and p-JAK2, which ameliorated the leptin resistance and restored the lean expression of appetite regulatory genes (Pomc and Agrp) in hypothalamus of OMI-F1 group. Taken together, these results indicate that reducing maternal Socs3 expression during pregnancy can attenuate obesity caused by the early life environment in mice, which may inspire therapies that enable obese mothers to bear metabolically healthy children.
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Affiliation(s)
- Feng Zhu
- Department of Graduate, Bengbu Medical College, Bengbu, China
- College of Biological and Chemical Science and Engineering, Jiaxing University, Jiaxing, China
- Children's Medical Center, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Dawei Zhang
- College of Biological and Chemical Science and Engineering, Jiaxing University, Jiaxing, China
| | - Fangfang Shen
- Children's Medical Center, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Ke Xu
- Children's Medical Center, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Xin Huang
- College of Biological and Chemical Science and Engineering, Jiaxing University, Jiaxing, China
| | - Jue Liu
- Children's Medical Center, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jin Zhang
- College of Biological and Chemical Science and Engineering, Jiaxing University, Jiaxing, China
| | - Yiqun Teng
- Department of Graduate, Bengbu Medical College, Bengbu, China
- Children's Medical Center, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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Al-Salihi M, Bornikoel A, Zhuang Y, Stachura P, Scheller J, Lang KS, Lang PA. The role of ADAM17 during liver damage. Biol Chem 2021; 402:1115-1128. [PMID: 34192832 DOI: 10.1515/hsz-2021-0149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/02/2021] [Indexed: 12/14/2022]
Abstract
A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.
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Affiliation(s)
- Mazin Al-Salihi
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- School of Medicine, University of Central Lancashire, Preston, PR1 2HE, UK
| | - Anna Bornikoel
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Yuan Zhuang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Pawel Stachura
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Jürgen Scheller
- Department of Biochemistry and Molecular Biology II, Medical Faculty, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
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Thibaut R, Gage MC, Pineda-Torra I, Chabrier G, Venteclef N, Alzaid F. Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease. FEBS J 2021; 289:3024-3057. [PMID: 33860630 PMCID: PMC9290065 DOI: 10.1111/febs.15877] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/05/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.
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Affiliation(s)
- Ronan Thibaut
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Matthew C Gage
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Inès Pineda-Torra
- Department of Medicine, Centre for Cardiometabolic and Vascular Science, University College London, UK
| | - Gwladys Chabrier
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Nicolas Venteclef
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Fawaz Alzaid
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
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Tang H, Fang H, Guo W, Cao S, Guo D, Zhang H, Gao J, Zhang S. Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy. Mol Biol Rep 2021; 48:1687-1695. [PMID: 33484391 PMCID: PMC7925450 DOI: 10.1007/s11033-020-06090-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 12/14/2020] [Indexed: 11/29/2022]
Abstract
Ischemia-reperfusion injury (IRI) is inevitable during liver surgery, and it is an important factor affecting the prognosis of patients. IL-6 rs1800796 single nucleotide polymorphisms (SNPs) can promote synthesis and secretion of IL-6 and protect hepatocytes from IRI. In this study, we investigated the mechanisms by which IL-6 alleviates hepatic IRI. We transfected lentivirus which carries IL-6 rs1800796 to L02 cells and constructed the cell line (L02-IL6) with a high expression of IL-6. The biological function of IL-6 SNPs was explored through a cell model of hypoxia-reoxygenation (H/R). Cell viability was evaluated by CCK8 and Real-Time Cell Analysis (RTCA), and found that the viability of the L02-IL6 cells was higher than that of the control group (P < 0.01). Flow cytometry assay showed that the rate of apoptosis was significantly decreased in L02-IL6 cells. Furthermore, in comparison with the control group, the level of cleaved-caspase3, which is an important marker of apoptosis, was dramatically decreased. These differences showed that the sequence variants at rs1800796 of the IL-6 gene could improve the resistance against H/R. Moreover, the levels of autophagy-related proteins, such as LC3 and Beclin-1, were upregulated in L02-IL6 group on H/R injury, which means IL-6 could alleviate apoptosis via activating the autophagy pathway. And we also found that the STAT3 signal pathway was activated. Next, we investigated whether the exogenous treatment with IL-6 affect hepatocytes and thus play a protective role. We pre-treated the L02 cells with recombinant human IL-6 for 12 h and then made H/R treatment. We found the treatment with 100 ng/ml IL-6 alleviated the damage of L02 cells and inhibited the apoptosis. And the further study revealed the pre-treatment with IL-6 activated the STAT3 signaling pathway in the L02 cells and then caused the activation of autophagy and apoptosis inhibition. IL-6 might play a critical role in alleviating hepatic IRI, through its modulation of the STAT3 signaling pathway, and activation of autophagy. Recombinant human IL-6 might be a potential therapeutic target in hepatic IRI.
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Affiliation(s)
- Hongwei Tang
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Hongbo Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shengli Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Guo
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Huapeng Zhang
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Jie Gao
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. .,Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China. .,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China.
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12
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Shao Q, Wu Y, Ji J, Xu T, Yu Q, Ma C, Liao X, Cheng F, Wang X. Interaction Mechanisms Between Major Depressive Disorder and Non-alcoholic Fatty Liver Disease. Front Psychiatry 2021; 12:711835. [PMID: 34966296 PMCID: PMC8710489 DOI: 10.3389/fpsyt.2021.711835] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Major depressive disorder (MDD), which is highly associated with non-alcoholic fatty liver disease (NAFLD), has complex pathogenic mechanisms. However, a limited number of studies have evaluated the mutual pathomechanisms involved in MDD and NAFLD development. Chronic stress-mediated elevations in glucocorticoid (GC) levels play an important role in the development of MDD-related NAFLD. Elevated GC levels can induce the release of inflammatory factors and changes in gut permeability. Elevated levels of inflammatory factors activate the hypothalamic-pituitary-adrenal (HPA) axis, which further increases the release of GC. At the same time, changes in gut permeability promote the release of inflammatory factors, which results in a vicious circle among the three, causing disease outbreaks. Even though the specific role of the thyroid hormone (TH) in this pathogenesis has not been fully established, it is highly correlated with MDD and NAFLD. Therefore, changing lifestyles and reducing psychological stress levels are necessary measures for preventing MDD-related NAFLD. Among them, GC inhibitors and receptor antagonists may be key in the alleviation of early and mid-term disease progression. However, combination medications may be important in late-stage diseases, but they are associated with various side effects. Traditional Chinese medicines have been shown to be potential therapeutic alternatives for such complex diseases.
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Affiliation(s)
- Qi Shao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yiping Wu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Ji
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tian Xu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qiaoyu Yu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chongyang Ma
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xuejing Liao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fafeng Cheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueqian Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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13
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Kim TH, Banini BA, Asumda FZ, Campbell NA, Hu C, Moser CD, Shire AM, Han S, Ma C, Krishnan A, Mounajjed T, White TA, Gores GJ, LeBrasseur NK, Charlton MR, Roberts LR. Knockout of sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2020; 319:G333-G344. [PMID: 32683952 PMCID: PMC7509257 DOI: 10.1152/ajpgi.00150.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sulfatase 2 (SULF2) is a heparan sulfate editing enzyme that regulates the milieu of growth factors and cytokines involved in a variety of cellular processes. We used a murine model of diet-induced steatohepatitis to assess the effect of SULF2 downregulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wild-type B6;129 mice (WT) and Sulf2-knockout B6;129P2-SULF2Gt(PST111)Byg mice (Sulf2-KO) were fed a fast-food diet (FFD) rich in saturated fats, cholesterol, and fructose or a standard chow diet (SC) ad libitum for 9 mo. WT mice on FFD showed a threefold increase in hepatic Sulf2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression compared with WT mice on SC. Knockout of Sulf2 led to a significant decrease in diet-mediated weight gain and dyslipidemia compared with WT mice on FFD. Knockout of Sulf2 also abrogated diet-induced steatohepatitis and hepatic fibrosis compared with WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFβR2 and PDGFRβ were significantly decreased in Sulf2-KO mice compared with WT mice on FFD. Together, our data suggest that knockout of Sulf2 significantly downregulates dyslipidemia, steatohepatitis, and hepatic fibrosis in a diet-induced mouse model of NAFLD, suggesting that targeting of SULF2 signaling may be a potential therapeutic mechanism in NASH.NEW & NOTEWORTHY We report for the first time that in wild-type (WT) mice, fast-food diet (FFD) induced a threefold increase in hepatic Sulf2 mRNA and a 2.2-fold increase in sulfatase 2 (SULF2) protein expression compared with WT mice on standard chow diet (SC). We showed that knockout of SULF2 ameliorates FFD-induced obesity, hyperlipidemia, steatohepatitis, and fibrosis. These data, along with work from other laboratories, suggest that SULF2 may be critical to the ability of the liver to progress to nonalcoholic steatohepatitis and fibrosis in conditions of overnutrition.
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Affiliation(s)
- Tae Hyo Kim
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota,2Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Bubu A. Banini
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Faizal Z. Asumda
- 3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Nellie A. Campbell
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Chunling Hu
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Catherine D. Moser
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Abdirashid M. Shire
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Shaoshan Han
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Chenchao Ma
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Anuradha Krishnan
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Taofic Mounajjed
- 4Division of Anatomic Pathology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Thomas A. White
- 5Robert & Arlene Kogod Center on Aging, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Gregory J. Gores
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Nathan K. LeBrasseur
- 4Division of Anatomic Pathology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Michael R. Charlton
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Lewis Rowland Roberts
- 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, and Mayo Clinic Cancer Center, Rochester, Minnesota
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14
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Anti-inflammatory Mechanism of Ruzu Bitters on Diet-Induced Nonalcoholic Fatty Liver Disease in Male Wistar Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:5246725. [PMID: 32774420 PMCID: PMC7395997 DOI: 10.1155/2020/5246725] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/13/2020] [Indexed: 01/17/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become notorious globally. Increasingly emerging evidence shows that NAFLD is strongly associated with inflammation, with proinflammatory cytokines such as interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) playing a vital role in its progression. In this work, an attempt was made to verify the anti-inflammatory activity of Ruzu herbal bitters (RHB), an antiobesity medicinal concoction, on NAFLD induced by a high-fat diet (HFD) in albino Wistar rats. Twenty-five (25) rats were divided into five groups as follows: Group 1, the normal control, was maintained on standard rat chow and received normal saline (1 ml/kg body weight (BW)/day) for twelve weeks. The other groups were maintained on HFD for twelve weeks. Thereafter, groups 2–5 were treated with pioglitazone (4 mg/kg BW/day), RHB (0.6 ml/kg BW/day), normal saline (1 ml/kg BW/day), and fenofibrate (10 mg/kg BW/day), respectively. The animals were sacrificed after the experimental period. Biochemical indicators of oxidative stress and inflammation were assayed in the liver according to standard methods. The histological features of the liver were also compared to assess liver damage. RHB significantly (p < 0.05) reduced body weight and liver index, inhibited oxidative stress, boosted antioxidant enzymes by increasing the activity and level of SOD and GSH, reduced proinflammatory markers (IL-2, IL-6, TNF-α), and reversed histological alterations induced by NAFLD in rat liver. In conclusion, the anti-inflammatory activity of RHB in the prevention of NAFLD in rats has been confirmed.
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15
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Ali SE, Waddington JC, Park BK, Meng X. Definition of the Chemical and Immunological Signals Involved in Drug-Induced Liver Injury. Chem Res Toxicol 2019; 33:61-76. [PMID: 31682113 DOI: 10.1021/acs.chemrestox.9b00275] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Idiosyncratic drug-induced liver injury (iDILI), which is rare and often recognized only late in drug development, poses a major public health concern and impediment to drug development due to its high rate of morbidity and mortality. The mechanisms of DILI are not completely understood; both non-immune- and immune-mediated mechanisms have been proposed. Non-immune-mediated mechanisms including direct damage to hepatocytes, mitochondrial toxicity, interference with transporters, and alteration of bile ducts are well-known to be associated with drugs such as acetaminophen and diclofenac; whereas immune-mediated mechanisms involving activation of both adaptive and innate immune cells and the interactions of these cells with parenchymal cells have been proposed. The chemical signals involved in activation of both innate and adaptive immune responses are discussed with respect to recent scientific advances. In addition, the immunological signals including cytokine and chemokines that are involved in promoting liver injury are also reviewed. Finally, we discuss how liver tolerance and regeneration can have profound impact on the pathogenesis of iDILI. Continuous research in developing in vitro systems incorporating immune cells with liver cells and animal models with impaired liver tolerance will provide an opportunity for improved prediction and prevention of immune-mediated iDILI.
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Affiliation(s)
- Serat-E Ali
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - James C Waddington
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - Xiaoli Meng
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
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16
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Siramolpiwat S, Punjachaipornpon T, Pornthisarn B, Vilaichone RK, Chonprasertsuk S, Tangaroonsanti A, Bhanthumkomol P, Phumyen A, Yasiri A, Kaewmanee M. N-Acetylcysteine Prevents Post-embolization Syndrome in Patients with Hepatocellular Carcinoma Following Transarterial Chemoembolization. Dig Dis Sci 2019; 64:3337-3345. [PMID: 31073737 DOI: 10.1007/s10620-019-05652-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Post-embolization syndrome is a common complication after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). N-acetylcysteine (NAC) is known to ameliorate liver damage from several causes. AIM To determine the efficacy of intravenous NAC in the prevention of post-embolization syndrome in HCC patients following TACE. METHODS In this study, patients with HCC admitted for TACE were prospectively enrolled. All patients were randomized stratified by Child A or B to receive NAC or placebo. The NAC group received intravenous NAC 24 h prior to TACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h, then continuous infusion 6.25 mg/h for 48 h after the procedure). The placebo group received an infusion of 5% glucose solution until 48 h after procedure. The post-embolization syndrome was defined as: T ≥ 38.5 c and serum ALT > 3 times of pretreatment value. RESULTS In total, 111 HCC patients were enrolled; 57 were randomly assigned to NAC group and 54 to placebo group. The incidence of post-embolization syndrome was lower in NAC group (24.6%) compared to placebo group (48.2%); P = 0.01. On multivariate analysis, receiving IV NAC (P = 0.03) and HCC diameter (P < 0.01) were associated with developing post-embolization syndrome. Post-TACE liver decompensation was documented in 26/111 (23.4%) patients. There was no difference in the incidence of post-TACE liver decompensation between NAC and placebo group. CONCLUSIONS In this study, intravenous NAC administration reduces the incidence of post-embolization syndrome after TACE in patients with HCC. However, it does not prevent post-TACE liver decompensation. TRIAL REGISTRATION NUMBER This study was registered with Thai Clinical Trial Registry (TCTR20150313002).
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Affiliation(s)
- Sith Siramolpiwat
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand. .,Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand.
| | - Thanachai Punjachaipornpon
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Bubpha Pornthisarn
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Ratha-Korn Vilaichone
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand.,Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Soonthorn Chonprasertsuk
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Anupong Tangaroonsanti
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Patommatat Bhanthumkomol
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Achara Phumyen
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Atipat Yasiri
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Mayurachat Kaewmanee
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
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17
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Saito H, Tanaka T, Sugahara M, Tanaka S, Fukui K, Wakashima T, Nangaku M. Inhibition of prolyl hydroxylase domain (PHD) by JTZ-951 reduces obesity-related diseases in the liver, white adipose tissue, and kidney in mice with a high-fat diet. J Transl Med 2019; 99:1217-1232. [PMID: 30952940 DOI: 10.1038/s41374-019-0239-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 01/16/2019] [Accepted: 01/28/2019] [Indexed: 12/11/2022] Open
Abstract
The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD). Eight-week-old, C57BL/6J mice were fed with HFD for 20 weeks with or without JTZ-951(0.005%; mixed in chow). Body weight and plasma non-high-density lipoprotein (HDL) cholesterol levels were significantly lower in the JTZ-951 group as compared with the vehicle group. PHD inhibition improved liver steatosis, macrophage infiltration into WAT and adipocyte fibrosis. In the kidney, PHD inhibition reduced albuminuria. Histologically, the number of F4/80- positive infiltrating macrophages and mesangial expansion were milder in the JTZ-951 group. Relative mRNA expression of adiponectin in WAT was higher in the JTZ-951-treated group and inversely correlated with hepatic steatosis score, adipocyte macrophage aggregation, and albuminuria. Activation of HIF ameliorates multiple obesity-related consequences in mice with HFD. The results of the present study offer the promising view that pharmacological PHD inhibition may be beneficial for the treatment of obesity-related diseases that can be ameliorated by weight loss.
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Affiliation(s)
- Hisako Saito
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tetsuhiro Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
| | - Mai Sugahara
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kenji Fukui
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Takeshi Wakashima
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
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18
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Spalinger MR, Atrott K, Baebler K, Schwarzfischer M, Melhem H, Peres DR, Lalazar G, Rogler G, Scharl M, Frey-Wagner I. Administration of the Hyper-immune Bovine Colostrum Extract IMM-124E Ameliorates Experimental Murine Colitis. J Crohns Colitis 2019; 13:785-797. [PMID: 30590526 DOI: 10.1093/ecco-jcc/jjy213] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/18/2018] [Accepted: 12/10/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease [IBD] is accompanied by lesions in the epithelial barrier, which allow translocation of bacterial products from the gut lumen to the host's circulation. IMM-124E is a colostrum-based product containing high levels of anti-E.coli-LPS IgG, and might limit exposure to bacterial endotoxins. Here, we investigated whether IMM-124E can ameliorate intestinal inflammation. METHODS Acute colitis was induced in WT C57Bl/6J mice by administration of 2.5% dextran sodium sulphate [DSS] for 7 days. T cell transfer colitis was induced via transfer of 0.5 x 106 naïve T cells into RAG2-/- C57Bl/6J mice. IMM-124E was administered daily by oral gavage, either preventively or therapeutically. RESULTS Treatment with IMM-124E significantly ameliorated colitis in acute DSS colitis and in T cell transfer colitis. Maximum anti-inflammatory effects were detected at an IMM-124E concentration of 100 mg/kg body weight, whereas 25 mg/kg and 500 mg/kg were less effective. Histology revealed reduced levels of infiltrating immune cells and less pronounced mucosal damage. Flow cytometry revealed reduced numbers of effector T helper cells in the intestine, whereas levels of regulatory T cells were enhanced. IMM-124E treatment reduced the DSS-induced increase of serum levels of lipopolysaccharide [LPS]-binding protein, indicating reduced systemic LPS exposure. CONCLUSIONS Our results demonstrate that oral treatment with IMM-124E significantly reduces intestinal inflammation, via decreasing the accumulation of pathogenic T cells and concomitantly increasing the induction of regulatory T cells. Our study confirms the therapeutic efficacy of IMM-124E in acute colitis and suggests that administration of IMM-124E might represent a novel therapeutic strategy to induce or maintain remission in chronic colitis.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Marlene Schwarzfischer
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Hassan Melhem
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | | | - Gadi Lalazar
- Laboratory of Cellular Biophysics, Rockefeller University, New York, NY, USA
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Isabelle Frey-Wagner
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
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19
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Lepidium meyenii Walp Exhibits Anti-Inflammatory Activity against ConA-Induced Acute Hepatitis. Mediators Inflamm 2018; 2018:8982756. [PMID: 30647537 PMCID: PMC6311815 DOI: 10.1155/2018/8982756] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/26/2018] [Indexed: 12/31/2022] Open
Abstract
Strong inflammation is a prominent pathogenesis of acute hepatitis, which can induce hepatocyte death and lead to liver failure. Lepidium meyenii Walp (Maca) is a traditional herbal medicine mostly used in improving sperm motility and serum hormone levels, etc. However, there are no reports that showed Maca was designed for treating hepatitis so far. Therefore, the protective effects and pharmacological mechanisms of Maca are unknown in hepatitis. In this study, we found that the protective effects of Maca extract ameliorate ConA-induced acute hepatitis (CIH) and underlying mechanisms. We determined that pretreatment with Maca extract significantly suppressed the production of aminotransferases and inflammatory cytokines, including IFN-γ, TNF-α, IL-1β, IL-2, IL-6, IL-12, and IL-17a, and moderated acute liver injury in CIH. Maca recruited more myeloid-derived suppressor cells (MDSCs) to the liver and suppressed infiltration of natural killer T cells (NKT cells) and macrophages in the liver. Furthermore, our data indicated the molecular mechanism of the inhibitory inflammatory effects of Maca, which should suppress the activation of NF-κB, IFN-γ/STAT1, and IL-6/STAT3 signalings. Collectively, this present research explores Maca as an effective hepatoprotective medicine to inhibit inflammation and liver injury caused by acute hepatitis.
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Karatayli E, Hall RA, Weber SN, Dooley S, Lammert F. Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury. Biochim Biophys Acta Mol Basis Dis 2018; 1865:298-307. [PMID: 30447270 DOI: 10.1016/j.bbadis.2018.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS ACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre-injured liver (Abcb4/Mdr2-/-) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model. METHOD Ten (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4-/- knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2-ΔΔCt method. IL6 and HGF plasma levels were quantified by ELISA. RESULTS Older mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels. CONCLUSION We propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4-/- mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.
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Affiliation(s)
- Ersin Karatayli
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Rabea A Hall
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity. Cytokine 2018; 124:154542. [PMID: 30241896 DOI: 10.1016/j.cyto.2018.09.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/01/2018] [Accepted: 09/07/2018] [Indexed: 12/15/2022]
Abstract
In their quiescent state, Hepatic stellate cells (HSCs), are present in the sub-endothelial space of Disse and have minimal interaction with immune cells. However, upon activation following injury, HSCs directly or indirectly interact with various immune cells that enter the space of Disse and thereby regulate diverse hepatic function and immune physiology. Other than the normal physiological functions of HSCs such as hepatic homeostasis, maturation and differentiation, they also participate in hepatic inflammation by releasing a battery of inflammatory cytokines and chemokines and interacting with other liver cells. Here, we have reviewed the role of HSC in the pathogenesis of liver inflammation and some infectious diseases in order to understand how the interplay between immune cells and HSCs regulates the overall outcome and disease pathology.
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22
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Prognostic role of haematological indices in sudden sensorineural hearing loss: Review and meta-analysis. Clin Chim Acta 2018; 483:104-111. [DOI: 10.1016/j.cca.2018.04.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/16/2018] [Accepted: 04/16/2018] [Indexed: 01/11/2023]
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Yang GC, Wei M, Li Z, Li B, Liang Y, Liu YP. Expression of cytokines in rats with ethanol-induced liver injury treated with Zhige oral solution. Shijie Huaren Xiaohua Zazhi 2018; 26:10-16. [DOI: 10.11569/wcjd.v26.i1.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the correlation between expression of cytokines and preventive effects of Zhige oral solution against alcoholic liver injury (ALI) in rats.
METHODS Rats were divided into six groups: normal control group, model group, positive control group, high-, medium-, and low-dose Zhige oral solution groups. Except the normal control group, ALI was induced in rats of other groups by simple alcohol gavage. The high-, medium-, and low-dose Zhige oral solution groups were given high-, medium- and low-dose group Zhige oral solution, the positive control group was given Jiejiuling oral solution, and the normal control group was given distilled water. Twelve weeks later, abdominal aorta arterial blood was collected to measure serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as the contents of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10. The rats were sacrificed to observe the pathological changes in liver tissue.
RESULTS Compared with the normal control group, serum levels of TNF-α, IL-6, IL-10, ALT, and AST were significantly altered in all groups except the high-dose Zhige oral solution group (P < 0.01 or 0.05), and varying degrees of massive swelling of liver cells and red lipid droplets were observed in liver tissues in all groups. Compared with the model group, all the tested indicators showed varying degrees of reversal in the positive control group and three intervention groups (P < 0.01 or 0.05), and the reversal effect was best in the high-dose Zhige oral solution group (P < 0.01). The therapeutic effect in the middle dose group was similar to that in the positive control group (P > 0.05).
CONCLUSION Zhige oral solution can reduce or inhibit the occurrence of ALI by regulating the levels of cytokines in rats.
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Affiliation(s)
- Guo-Chuan Yang
- Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Mei Wei
- Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Zhi Li
- Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Bo Li
- Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yang Liang
- Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - You-Ping Liu
- Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou 646000, Sichuan Province, China
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Li H, Toth E, Cherrington NJ. Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH. Toxicol Sci 2018; 161:23-33. [PMID: 29145614 PMCID: PMC6454421 DOI: 10.1093/toxsci/kfx253] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In the past few decades, great conceptual and technological advances have been made in the field of toxicology, but animal model-based research still remains one of the most widely used and readily available tools for furthering our current knowledge. However, animal models are not perfect in predicting all systemic toxicity in humans. Extrapolating animal data to accurately predict human toxicities remains a challenge, and researchers are obligated to question the appropriateness of their chosen animal model. This paper provides an assessment of the utility of the methionine- and choline-deficient (MCD) diet fed animal model in reflecting human nonalcoholic steatohepatitis (NASH) and the potential risks of adverse drug reactions and toxicities that are associated with the disease. As a commonly used NASH model, the MCD model fails to exhibit most metabolic abnormalities in a similar manner to the human disease. The MCD model, on the other hand, closely resembles human NASH histology and reflects signatures of drug transporter alterations in humans. Due to the nature of the MCD model, it should be avoided in studies of NASH pathogenesis, metabolic parameter evaluation, and biomarker identification. But it can be used to accurately predict altered drug disposition due to NASH-associated transporter alterations.
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Affiliation(s)
- Hui Li
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
| | - Erica Toth
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
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25
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Zimmers TA, Jin X, Zhang Z, Jiang Y, Koniaris LG. Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice. Am J Physiol Endocrinol Metab 2017; 313:E440-E449. [PMID: 28655714 PMCID: PMC5668597 DOI: 10.1152/ajpendo.00032.2017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/01/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023]
Abstract
Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.
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Affiliation(s)
- Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Xiaoling Jin
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Zongxiu Zhang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Yanlin Jiang
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana;
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
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Berlian G, Tandrasasmita OM, Tjandrawinata RR. Trombinol, a bioactive fraction of Psidium guajava , stimulates thrombopoietin expression in HepG2 cells. Asian Pac J Trop Biomed 2017. [DOI: 10.1016/j.apjtb.2016.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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27
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Effect of luteolin on inflammatory responses in RAW264.7 macrophages activated with LPS and IFN-γ. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.02.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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28
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Rabadán-Chávez GM, Miliar Garcia A, Paniagua Castro N, Escalona Cardoso G, Quevedo-Corona L, Reyes-Maldonado E, Jaramillo-Flores ME. Modulating the expression of genes associated with hepatic lipid metabolism, lipoperoxidation and inflammation by cocoa, cocoa extract and cocoa flavanols related to hepatic steatosis induced by a hypercaloric diet. Food Res Int 2016. [DOI: 10.1016/j.foodres.2016.03.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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de Andrade DC, de Carvalho SN, Pinheiro D, Thole AA, Moura AS, de Carvalho L, Cortez EAC. Bone marrow mononuclear cell transplantation improves mitochondrial bioenergetics in the liver of cholestatic rats. Exp Cell Res 2015; 336:15-22. [PMID: 25978973 DOI: 10.1016/j.yexcr.2015.05.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 04/30/2015] [Accepted: 05/04/2015] [Indexed: 12/28/2022]
Abstract
Mitochondrial dysfunction has been associated with liver cholestatis. Toxic bile salt accumulation leads to chronic injury with mitochondrial damage, ROS increase and apoptosis, resulting in liver dysfunction. This study aimed to analyze mitochondrial bioenergetics in rats with hepatic fibrosis induced by bile duct ligation (BDL) after BMMNC transplantation. Livers were collected from normal rats, fibrotic rats after 14 and 21 days of BDL (F14d and F21d) and rats that received BMMNC at 14 days of BDL, analyzed after 7 days. F21d demonstrated increased collagen I content and consequently decrease after BMMNC transplantation. Both F14d and F21d had significantly reduced mitochondrial oxidation capacity and increased mitochondrial uncoupling, which were restored to levels similar to those of normal group after BMMNC transplantation. In addition, F21d had a significantly increase of UCP2, and reduced PGC-1α content. However, after BMMNC transplantation both proteins returned to levels similar to normal group. Moreover, F14d had a significantly increase in 4-HNE content compared to normal group, but after BMMNC transplantation 4-HNE content significantly reduced, suggesting oxidative stress reduction. Therefore, BMMNC transplantation has a positive effect on hepatic mitochondrial bioenergetics of cholestatic rats, increasing oxidative capacity and reducing oxidative stress, which, in turn, contribute to liver function recover.
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Affiliation(s)
- Daniela Caldas de Andrade
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil
| | - Simone Nunes de Carvalho
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil
| | - Daphne Pinheiro
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil
| | - Alessandra Alves Thole
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil
| | - Anibal Sanchez Moura
- Labotatory of Nutrition and Development Physiology, Department of Physiological Sciences, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 5° andar, 20550-170 Rio de Janeiro, Brazil
| | - Lais de Carvalho
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil
| | - Erika Afonso Costa Cortez
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology, State University of Rio de Janeiro, UERJ, Av. Prof. Manoel de Abreu 444, 3° andar, 20550-170 Rio de Janeiro, Brazil.
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Xin G, Qin S, Wang S, Wang X, Zhang Y, Wang J. Sex hormone affects the severity of non-alcoholic steatohepatitis through the MyD88-dependent IL-6 signaling pathway. Exp Biol Med (Maywood) 2015; 240:1279-86. [PMID: 25790822 DOI: 10.1177/1535370215570189] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 12/01/2014] [Indexed: 01/09/2023] Open
Abstract
Recent research has shown that the occurrence of gender disparity in liver cancer associated with sex differences in MyD88-dependent IL-6 production, but the role of this signaling pathway in sex differences of non-alcoholic steatohepatitis (NASH) remains unknown. To investigate the effects of sex hormone-specific intervention on pathology and progression of NASH, and on the inflammatory TLR-MyD88-IL-6 signaling pathway NASH was modeled in C57/BL6 mice by feeding a methionine and choline-deficient (MCD) diet for 4 weeks. Male mice were subjected to sex hormone-related interventions such as orchidectomy, and orchidectomy combined with administration of either testosterone propionate or estradiol benzoate. Next, the degree of non-alcoholic fatty liver disease activity score (NAS), serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the expression level of MyD88 and IL-6, were compared between these groups. Males developed more serious inflammatory problems and had a higher NAS than the females. Sex-specific intervention in male mice by orchidectomy reduced NAS, ALT, and AST, and the expression level of MyD88 and IL-6. But administration of exogenous androgen had no influence on either NAS or the expression of ALT, AST, MyD88, and IL-6. On the other hand, exogenous estrogen could alleviate the pathological damage caused by NASH, as well as reduce NAS, ALT and AST, and the expression of MyD88 and IL-6. The result show different sex hormone-related interventions affected the severity of NASH, possibly by modulating the level of sex hormones and regulating the TLR-MyD88-IL-6 signaling pathway.
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Affiliation(s)
- Guangda Xin
- Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
| | - Shaoyou Qin
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
| | - Song Wang
- Department of Urology, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xu Wang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
| | - Yonggui Zhang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
| | - Jiangbin Wang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
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Yamaguchi K, Nishimura T, Ishiba H, Seko Y, Okajima A, Fujii H, Tochiki N, Umemura A, Moriguchi M, Sumida Y, Mitsuyoshi H, Yasui K, Minami M, Okanoue T, Itoh Y. Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice. Liver Int 2015; 35:550-61. [PMID: 25066281 DOI: 10.1111/liv.12645] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 07/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Mice fed high-fat diet (HFD) demonstrate obesity-related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)-6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver. METHODS Plasma markers of IR and hepatic IL-6 signalling were examined in eight-week HFD feeding C57/BL6 mice. Furthermore, IR-related molecules in skeletal muscles, adipose tissues and livers were investigated following a single injection of anti- IL-6 receptor neutralizing antibody (MR16-1) in two-week HFD feeding mice. To investigate the role of IL-6 in hepatic steatosis by prolonged HFD, hepatic triglyceride accumulation was assessed in eight-week HFD feeding mice with continuous MR16-1 treatment. RESULTS High-fat diet for both 2 and 8 weeks elevated plasma IL-6, insulin and leptin, which were decreased by MR16-1 treatment. A single injection of MR16-1 ameliorated IR as assessed by glucose and insulin tolerance test, which may be attributable to upregulation of glucose transporter type 4 via phosphorylation of AMP-activated protein kinase as well as upregulation of peroxisome proliferator-activated receptor alpha in livers and, particularly, in skeletal muscles. MR16-1 also decreased mRNA expression of leptin and tumour necrosis factor-alpha and increased that of adiponectin in adipose tissue. High-fat diet for 8 weeks, not 2 weeks, induced hepatic steatosis and increased hepatic triglyceride content, all of which were ameliorated by MR16-1 treatment. CONCLUSIONS Blockade of excessive IL-6 stimulus ameliorated HFD-induced IR in a skeletal muscle and modulated the production of adipokines from an early stage of NAFLD, leading to prevention of liver steatosis for a long term.
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Affiliation(s)
- Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Devanaboyina SC, Lynch SM, Ober RJ, Ram S, Kim D, Puig-Canto A, Breen S, Kasturirangan S, Fowler S, Peng L, Zhong H, Jermutus L, Wu H, Webster C, Ward ES, Gao C. The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics. MAbs 2015; 5:851-9. [PMID: 24492341 DOI: 10.4161/mabs.26389] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
A drawback of targeting soluble antigens such as cytokines or toxins with long-lived antibodies is that such antibodies can prolong the half-life of the target antigen by a "buffering" effect. This has motivated the design of antibodies that bind to target with higher affinity at near neutral pH relative to acidic endosomal pH (~pH 6.0). Such antibodies are expected to release antigen within endosomes following uptake into cells, whereas antibody will be recycled and exocytosed in FcRn-expressing cells. To understand how the pH dependence of antibody-antigen interactions affects intracellular trafficking, we generated three antibodies that bind IL-6 with different pH dependencies in the range pH 6.0-7.4. The behavior of antigen in the presence of these antibodies has been characterized using a combination of fixed and live cell fluorescence microscopy. As the affinity of the antibody:IL-6 interaction at pH 6.0 decreases, an increasing amount of antigen dissociates from FcRn-bound antibody in early and late endosomes, and then enters lysosomes. Segregation of antibody and FcRn from endosomes in tubulovesicular transport carriers (TCs) into the recycling pathway can also be observed in live cells, and the extent of IL-6 association with TCs correlates with increasing affinity of the antibody:IL-6 interaction at acidic pH. These analyses result in an understanding, in spatiotemporal terms, of the effect of pH dependence of antibody-antigen interactions on subcellular trafficking and inform the design of antibodies with optimized binding properties for antigen elimination.
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Affiliation(s)
| | - Sandra M Lynch
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA
| | - Raimund J Ober
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX, USA
| | - Sripad Ram
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX, USA
| | - Dongyoung Kim
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX, USA
| | - Alberto Puig-Canto
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA
| | - Shannon Breen
- Department of Oncology; Medimmune; Gaithersburg, MD, USA
| | - Srinath Kasturirangan
- Department of Antibody Discovery & Protein Engineering; Medimmune; Gaithersburg, MD, USA
| | - Susan Fowler
- Department of Antibody Discovery & Protein Engineering; Medimmune; Granta Park, Cambridge, UK
| | - Li Peng
- Department of Antibody Discovery & Protein Engineering; Medimmune; Gaithersburg, MD, USA
| | - Haihong Zhong
- Department of Oncology; Medimmune; Gaithersburg, MD, USA
| | - Lutz Jermutus
- Department of Antibody Discovery & Protein Engineering; Medimmune; Granta Park, Cambridge, UK
| | - Herren Wu
- Department of Antibody Discovery & Protein Engineering; Medimmune; Gaithersburg, MD, USA
| | - Carl Webster
- Department of Antibody Discovery & Protein Engineering; Medimmune; Granta Park, Cambridge, UK
| | - E Sally Ward
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX, USA
| | - Changshou Gao
- Department of Antibody Discovery & Protein Engineering; Medimmune; Gaithersburg, MD, USA
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Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070-18091. [PMID: 25561778 PMCID: PMC4277948 DOI: 10.3748/wjg.v20.i48.18070] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/21/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
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Pawlak M, Baugé E, Bourguet W, De Bosscher K, Lalloyer F, Tailleux A, Lebherz C, Lefebvre P, Staels B. The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology 2014; 60:1593-606. [PMID: 24995693 DOI: 10.1002/hep.27297] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 07/01/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. CONCLUSION The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression.
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Affiliation(s)
- Michal Pawlak
- European Genomic Institute for Diabetes, Lille, France; INSERM UMR1011, F-59000, Lille, France; University Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France
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Luo ZL, Tang LJ, Wang T, Dai RW, Ren JD, Cheng L, Xiang K, Tian FZ. Effects of treatment with hydrogen sulfide on methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol 2014; 29:215-222. [PMID: 24117897 DOI: 10.1111/jgh.12389] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2013] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Oxidative stress and inflammation play important roles in the progression from simple fatty liver to non-alcoholic steatohepatitis (NASH). The aim of this work was to investigate whether treatment with hydrogen sulfide (H2 S) prevented NASH in rats through abating oxidative stress and suppressing inflammation. METHODS A methionine-choline-deficient (MCD) diet rat model was prepared. Rats were divided into three experimental groups and fed for 8 weeks as follows: (i) control rats; (ii) MCD-diet-fed rats; (iii) MCD-diet-fed rats treated with NaHS (intraperitoneal injection of 0.1 mL/kg/day of 0.28 mol/L NaHS, a donor of H2 S). RESULTS MCD diet impaired hepatic H2 S biosynthesis in rats. Treatment with H2 S prevented MCD-diet-induced NASH, as evidenced by hematoxylin and eosin staining, reduced apoptosis and activities of alanine aminotransferase and aspartate aminotransferase, and attenuated hepatic fat accumulation in rats. Treatment with H2 S abated MCD-diet-induced oxidative stress through reducing cytochrome p4502E1 expression, enhancing heme oxygenase-1 expression, and suppressing mitochondrial reactive oxygen species formation, and suppressed MCD-diet-induced inflammation through suppressing activated nuclear factor κB signaling and reducing interleukin-6 and tumor necrosis factor α expressions. In addition, treatment of MCD-diet fed rats with H2 S had a beneficial modulation on expression profiles of fatty acid metabolism genes in livers. CONCLUSIONS Treatment with H2 S prevented NASH induced by MCD diet in rats possibly through abating oxidative stress and suppressing inflammation.
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Affiliation(s)
- Zhu-Lin Luo
- Department of General Surgery, General Hospital of Chengdu Military Command, Chengdu, Sichuan Province, China; Graduate School, The Third Military Medical University, Chongqing, China
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Neutrophil-to-Lymphocyte Ratio as a New, Quick, and Reliable Indicator for Predicting Diagnosis and Prognosis of Idiopathic Sudden Sensorineural Hearing Loss. Otol Neurotol 2013; 34:1400-4. [DOI: 10.1097/mao.0b013e31829b57df] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Abstract
Immune and inflammatory pathways have a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Both the innate and adaptive immune systems contribute to the development of NAFLD. Pathogen-associated molecular patterns and danger-associated molecular patterns are known to activate a variety of pattern-recognition receptors that result in inflammation. The key features of the immune system and inflammatory pathways in the development of NAFLD are discussed in this review.
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Affiliation(s)
- Michal Ganz
- Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605 USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605 USA
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Tan TCH, Crawford DHG, Jaskowski LA, Murphy TL, Santrampurwala N, Crane D, Clouston AD, Subramaniam VN, Anderson GJ, Fletcher LM. A corn oil-based diet protects against combined ethanol and iron-induced liver injury in a mouse model of hemochromatosis. Alcohol Clin Exp Res 2013; 37:1619-31. [PMID: 23742171 DOI: 10.1111/acer.12155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 02/18/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Combined iron overload and alcohol may promote synergistic chronic liver injury and toxicity. The role of specific dietary fats in influencing the development of co-toxic alcoholic liver disease needs further evaluation and is investigated in this study. METHODS Wild-type (WT) and the iron-loaded Hfe-null (Hfe(-/-) ) mice were fed chow (CC), a AIN-93G standard control (SC), or a corn oil-modified, AIN-93G-based (CO) diet with or without the addition of 20% ethanol (EtOH) in the drinking water for 8 weeks and assessed for liver injury. RESULTS WT mice on CC, SC, and CO diets had no liver injury, although mild steatosis developed in the SC and CO groups. The addition of EtOH resulted in mild steatohepatitis in WT mice fed SC but not those on a CO diet. EtOH administration in Hfe(-/-) animals on the CC and SC diets caused marked oxidative stress, inflammatory activity, and subsinusoidal and portal-portal tract linkage fibrosis with significant up-regulation of genes involved in cellular stress signaling and fibrogenic pathways. These effects were abrogated in the CO-fed mice, despite elevated serum EtOH levels and hepatic iron concentrations, reduced hepatic glutathione and mitochondrial superoxide dismutase activities. Feeding with the CO diet led to increased hepatic glutathione peroxidase and catalase activities and attenuated alcohol-induced hepatic steatosis in the Hfe(-/-) animals. Iron and EtOH feeding markedly reduced p-STAT3 and p-AMPK protein levels, but this effect was significantly attenuated when a CO diet was consumed. CONCLUSIONS A CO-based diet is protective against combined EtOH- and iron-induced liver toxicity, likely via attenuation of hepatic steatosis and oxidative stress and may have a role in the prevention of fibrosis development in chronic liver disease.
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Affiliation(s)
- Terrence C H Tan
- School of Medicine, University of Queensland, Brisbane, Queensland, Australia; Gallipoli Medical Research Centre, Greenslopes Hospital, Brisbane, Queensland, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
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Hatting M, Zhao G, Schumacher F, Sellge G, Al Masaoudi M, Gaβler N, Boekschoten M, Müller M, Liedtke C, Cubero FJ, Trautwein C. Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. Hepatology 2013; 57:2189-201. [PMID: 23339067 DOI: 10.1002/hep.26271] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 12/14/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Δhep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Δhep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Δhep) livers. CONCLUSION Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201).
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Affiliation(s)
- Maximilian Hatting
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
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Masuda M, Kanzaki S, Minami S, Kikuchi J, Kanzaki J, Sato H, Ogawa K. Correlations of inflammatory biomarkers with the onset and prognosis of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2013; 33:1142-50. [PMID: 22872174 DOI: 10.1097/mao.0b013e3182635417] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
HYPOTHESIS We investigated whether inflammatory biomarkers and stress are involved in the pathophysiology of idiopathic sensorineural hearing loss (ISHL). STUDY DESIGN Individual cohort study. SETTING Two tertiary centers. PATIENTS Forty-three ISHL and 10 non-ISHL patients seen in our ENT departments from 2004 to 2010 within a week from the onset of new symptoms and without steroid administration before visiting our departments. INTERVENTION Multiple audiologic evaluations, blood tests including leukocyte counts, natural killer cell activity (NKCA), interleukin 6 (IL-6), tumor necrosis factor, high-sensitivity CRP (hCRP), and the General Health Questionnaire were used to evaluate the systemic stress and inflammatory response. MAIN OUTCOME MEASURES Correlations between biomarkers and ISHL severity and prognosis were evaluated by statistical analysis. RESULTS In the ISHL patients, a neutrophil count above the reference range was associated with severe hearing loss and poor prognosis, and was accompanied by low NKCA and high IL-6. In the non-ISHL patients, these associations were not present. The abnormal neutrophil count was independent of preexisting vascular diseases. The abnormal counts responded to treatment and decreased into the reference range. CONCLUSION Neutrophil counts above the reference range of a facility will be a useful indicator of poor prognosis of ISHL. Synchronism of different types of NF-κB activation pathways could be required to cause severe ISHL. An NKCA decrease, an acute neutrophil count increase, and an IL-6 increase can induce NF-κB activation in the cochlea and cause severe ISHL. Further epidemiologic surveys should be conducted to evaluate whether stressful life events increase the risk of severe ISHL onset.
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Affiliation(s)
- Masatsugu Masuda
- Department of Otolaryngology, School of Medicine, Keio University, Tokyo, Japan.
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Bugelski PJ, Martin PL. Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets. Br J Pharmacol 2012; 166:823-46. [PMID: 22168282 PMCID: PMC3417412 DOI: 10.1111/j.1476-5381.2011.01811.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 10/14/2011] [Accepted: 11/28/2011] [Indexed: 12/20/2022] Open
Abstract
Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.
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Affiliation(s)
- Peter J Bugelski
- Biologics Toxicology, Janssen Research & Development, division of Johnson & Johnson Pharmaceutical Research & Development, LLC, Radnor, PA 19087, USA
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Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol 2012; 18:727-35. [PMID: 22371632 PMCID: PMC3286135 DOI: 10.3748/wjg.v18.i8.727] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 07/27/2011] [Accepted: 08/04/2011] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.
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Yimin, Furumaki H, Matsuoka S, Sakurai T, Kohanawa M, Zhao S, Kuge Y, Tamaki N, Chiba H. A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein. J Transl Med 2012; 92:265-81. [PMID: 22064320 DOI: 10.1038/labinvest.2011.159] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-α mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-α and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-α and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.
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Affiliation(s)
- Yimin
- Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Wei J, Shi M, Wu WQ, Xu H, Wang T, Wang N, Ma JL, Wang YG. IκB kinase-beta inhibitor attenuates hepatic fibrosis in mice. World J Gastroenterol 2011; 17:5203-13. [PMID: 22215946 PMCID: PMC3243888 DOI: 10.3748/wjg.v17.i47.5203] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 11/30/2011] [Accepted: 12/07/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis.
METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeIand type III collagen proteins and mRNA.
RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeIcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type III collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05).
CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.
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Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AMK, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 2011; 17:1481-9. [PMID: 22037645 PMCID: PMC4286294 DOI: 10.1038/nm.2513] [Citation(s) in RCA: 675] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Accepted: 09/15/2011] [Indexed: 12/23/2022]
Abstract
Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.
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Affiliation(s)
- Helga Ellingsgaard
- Clinic for Endocrinology, Diabetes & Metabolism and Department Biomedicine, University Hospital Basel, Basel, Switzerland.
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