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Wilson RB, Chen YJ, Zhang R, Maini S, Andrews TS, Wang R, Borradaile NM. Elongation factor 1A1 inhibition elicits changes in lipid droplet size, the bulk transcriptome, and cell type-associated gene expression in MASLD mouse liver. Am J Physiol Gastrointest Liver Physiol 2024; 327:G608-G622. [PMID: 39136056 PMCID: PMC11482270 DOI: 10.1152/ajpgi.00276.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 09/19/2024]
Abstract
Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a 2-wk intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) [129S6/SvEvTac mice fed Western diet (42% fat) for 26 wk]. Here, we further characterized the hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA sequencing (RNA-Seq) followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.NEW & NOTEWORTHY Chemical inhibition of EEF1A1 decreases hepatic lipid droplet size and decreases gene expression signatures associated with liver cell types that contribute to MASLD progression. Furthermore, changes in hepatic gene expression are primarily attributable to hepatocytes and cholangiocytes. This work highlights the therapeutic potential of targeting EEF1A1 in the setting of MASLD, and the utility of RNA-Seq deconvolution to reveal valuable information about tissue cell type composition and cell type-associated gene expression from bulk RNA-Seq data.
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Affiliation(s)
- Rachel B Wilson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Yun Jin Chen
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Richard Zhang
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Siddhant Maini
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Tallulah S Andrews
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Rennian Wang
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Nica M Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Jung W, Asaduddin M, Keum H, Son Y, Yoo D, Kim D, Lee S, Lee DY, Roh J, Park SH, Jon S. Longitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2305830. [PMID: 38459924 DOI: 10.1002/adma.202305830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.
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Affiliation(s)
- Wonsik Jung
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Muhammad Asaduddin
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Hyeongseop Keum
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Youngju Son
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Dohyun Yoo
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Dohyeon Kim
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Seojung Lee
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Dong Yun Lee
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul, 05505, South Korea
| | - Jin Roh
- Department of Pathology, Ajou University School of Medicine, 164 Worldcup-ro, Suwon, 16499, South Korea
| | - Sung-Hong Park
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
| | - Sangyong Jon
- Department of Biological Sciences, Center for Precision Bio-Nanomedicine, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, South Korea
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López-Pascual E, Rienda I, Perez-Rojas J, Rapisarda A, Garcia-Llorens G, Jover R, Castell JV. Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways. Int J Mol Sci 2024; 25:5203. [PMID: 38791241 PMCID: PMC11121209 DOI: 10.3390/ijms25105203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/02/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP's map road as well.
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Affiliation(s)
- Ernesto López-Pascual
- Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
- Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Ivan Rienda
- Pathology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - Judith Perez-Rojas
- Pathology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - Anna Rapisarda
- Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
- Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Guillem Garcia-Llorens
- Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ramiro Jover
- Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
- Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José V. Castell
- Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
- Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Microvesicular Steatosis in Individuals with Obesity: a Histological Marker of Non-alcoholic Fatty Liver Disease Severity. Obes Surg 2023; 33:813-820. [PMID: 36694089 DOI: 10.1007/s11695-023-06467-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/07/2023] [Accepted: 01/16/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND In non-alcoholic fatty liver disease (NAFLD), steatosis can manifest through two distinct forms: macrovesicular (macroS) and microvesicular (microS). OBJECTIVE To investigate the prevalence of microS and its association with biochemical parameters and NAFLD-related histological findings in individuals with obesity. METHODS This is an observational retrospective cross-sectional study, enrolling individuals who underwent bariatric surgery and liver biopsy at a university hospital. A 1:2 propensity matching was performed to pair microS with isolated macroS; this matching enrolled variables "age," "gender," "body mass index (BMI)," and "obesity-associated medical problems." Clinical, biochemical, and histopathological aspects were then analyzed and compared. RESULTS Of 115 participants, 88.7% were female; average age was 40.5 ± 5 years and mean BMI was 37.9 ± 3.3 kg/m2. Steatosis occurred in 82.6% (67.8% isolated macroS and 14.8% microS). MicroS is significantly associated with higher levels of alanine aminotransferase (ALT) (39.8 ± 26.4 vs. 26.7 ± 17.5; p = 0.04) and glucose (103.8 ± 52.6 vs. 83.3 ± 10.8; p = 0.03) and higher frequencies of moderate to severe macroS (41.2% vs. 2.0%; p < 0.001), portal fibrosis (100% vs. 50%; p < 0.001), perisinusoidal fibrosis (100% vs. 55.9%; p < 0.001), lobular inflammation (100% vs. 41.1%; p < 0.001), and portal inflammation (100% vs. 41.1%; p < 0.001). An independently positive association was observed between intensities of microS and macroS (p < 0.001). CONCLUSION MicroS is significantly associated with higher levels of ALT and glucose and higher frequencies of moderate to severe macroS, hepatocellular ballooning, portal fibrosis, perisinusoidal fibrosis, lobular inflammation, and portal inflammation. These findings indicate that microS could be considered a reliable histological marker of NAFLD severity.
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Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models. Clin Pharmacokinet 2022; 61:1251-1270. [PMID: 35699913 PMCID: PMC9439993 DOI: 10.1007/s40262-022-01132-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 11/24/2022]
Abstract
Background Obesity is associated with physiological changes that can affect drug pharmacokinetics. Obese individuals are underrepresented in clinical trials, leading to a lack of evidence-based dosing recommendations for many drugs. Physiologically based pharmacokinetic (PBPK) modelling can overcome this limitation but necessitates a detailed description of the population characteristics under investigation. Objective The purpose of this study was to develop and verify a repository of the current anatomical, physiological, and biological data of obese individuals, including population variability, to inform a PBPK framework. Methods A systematic literature search was performed to collate anatomical, physiological, and biological parameters for obese individuals. Multiple regression analyses were used to derive mathematical equations describing the continuous effect of body mass index (BMI) within the range 18.5–60 kg/m2 on system parameters. Results In total, 209 studies were included in the database. The literature reported mostly BMI-related changes in organ weight, whereas data on blood flow and biological parameters (i.e. enzyme abundance) were sparse, and hence physiologically plausible assumptions were made when needed. The developed obese population was implemented in Matlab® and the predicted system parameters obtained from 1000 virtual individuals were in agreement with observed data from an independent validation obese population. Our analysis indicates that a threefold increase in BMI, from 20 to 60 kg/m2, leads to an increase in cardiac output (50%), liver weight (100%), kidney weight (60%), both the kidney and liver absolute blood flows (50%), and in total adipose blood flow (160%). Conclusion The developed repository provides an updated description of a population with a BMI from 18.5 to 60 kg/m2 using continuous physiological changes and their variability for each system parameter. It is a tool that can be implemented in PBPK models to simulate drug pharmacokinetics in obese individuals.
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Affiliation(s)
- Mattia Berton
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. .,University of Basel, Basel, Switzerland.
| | - Sara Bettonte
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | | | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
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Saha M, Manna K, Das Saha K. Melatonin Suppresses NLRP3 Inflammasome Activation via TLR4/NF-κB and P2X7R Signaling in High-Fat Diet-Induced Murine NASH Model. J Inflamm Res 2022; 15:3235-3258. [PMID: 35668917 PMCID: PMC9166960 DOI: 10.2147/jir.s343236] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 03/29/2022] [Indexed: 12/17/2022] Open
Abstract
Background NLRP3 inflammasome activation plays a critical role in mediating inflammation and NASH (non-alcoholic steatohepatitis) progression that ultimately leads to cirrhosis and hepatocellular carcinoma. Melatonin (MLT) controls high-fat diet-induced NASH in the murine model by modulating NLRP3 mediated inflammation. P2X7R-mediated inflammasome activation is reported in several inflammatory models including NASH. Objective The role of MLT in P2X7R-mediated inflammation in the NASH model has not yet been explored. The present study investigated the role of MLT in amending high-fat diet-induced nonalcoholic steatohepatitis in the murine liver. Methods To evaluate the hepatological changes, mice were divided into four groups to investigate the improvement potential of this MLT (10 and 20 mg/kg) and to assess the experimental findings. Histology, biochemical assays, ELISA, FACS analysis, Western blotting, and IF were performed to assess the physical and molecular changes upon melatonin treatment. Results The result demonstrated that MLT administration reduced HFD (high-fat diet)-induced non-alcoholic steatohepatitic indices, which successively restored the hepatic morphological architecture and other pathophysiological features too. Moreover, the application of MLT suppressed HFD-induced activation of the inflammasome and through TLR4/NF-κB signaling. Herein, we report that MLT significantly suppresses P2X7R expression and calcium influx along with inflammasome in both in vitro and in vivo. The docking study revealed a strong binding affinity of MLT with P2X7R. Moreover, the results also showed that the Nrf2 level was boosted which may normalize the expression of antioxidant proteins that safeguard against oxidative damage triggered by inflammation. Furthermore, some matrix metalloproteinases like MMP 2 and MMP 9 were repressed and TIMP-1 level was increased, which also signifies that MLT could improve liver fibrosis in this model. Conclusion Based on our findings, this study may conclude that MLT could be used as a therapeutic agent in the high-fat diet-induced NASH model as it has persuasive anti-inflammatory potential.
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Affiliation(s)
- Moumita Saha
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
| | - Krishnendu Manna
- Department of Food and Nutrition, University of Kalyani, Kalyani, West Bengal, India
| | - Krishna Das Saha
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
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Lee D, Trinh TA, Shin MS, Kang KS. Adipose tissue. RECENT ADVANCEMENTS IN MICROBIAL DIVERSITY 2022:209-228. [DOI: 10.1016/b978-0-12-822368-0.00009-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Eskridge W, Vierling JM, Gosbee W, Wan GA, Hyunh ML, Chang HE. Screening for undiagnosed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): A population-based risk factor assessment using vibration controlled transient elastography (VCTE). PLoS One 2021; 16:e0260320. [PMID: 34847156 PMCID: PMC8631660 DOI: 10.1371/journal.pone.0260320] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/07/2021] [Indexed: 12/14/2022] Open
Abstract
The screening for undiagnosed non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (SUNN) study was a population-based screening study that aimed to provide proof of concept to encourage community-level screening and detection for this non-communicable disease. Current screening guidelines do not recommend the routine screening of nonalcoholic fatty liver disease (NAFLD) for asymptomatic populations, so providers are not encouraged to actively seek disease, even in high-risk patients. This study sought to determine whether a self-selecting cohort of asymptomatic individuals would have scores based on vibration controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) significantly correlated to risk factors to suggest that routine screening for high-risk patients should be recommended. The study recruited 1,070 self-selected participants in Houston and Galveston County, Texas, 940 of which were included in final analysis. A pre-screening survey was used to determine eligibility. VCTE-based scores analyzed steatosis and fibrosis levels. Fifty-seven percent of the study population demonstrated steatosis without fibrosis, suggesting NAFLD, while 16% demonstrated both steatosis and fibrosis, suggesting NASH. Statistically significant risk factors included factors related to metabolic syndrome, race, and age, while statistically significant protective factors included consumption of certain foods and exercise. The findings of this study suggest that high-risk individuals should be screened for NAFLD even in the absence of symptoms and that community-based screenings are an effective tool, particularly in the absence of proactive guidelines for providers.
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Affiliation(s)
- Wayne Eskridge
- Fatty Liver Foundation, Boise, Idaho, United States of America
| | - John M Vierling
- Section of Gastroenterology and Hepatology and Division of Abdominal Transplantation, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, Texas, United States of America
| | - Wayne Gosbee
- Link2Labs, Houston, Texas, United States of America
| | - Gabriella A Wan
- Fatty Liver Foundation, Boise, Idaho, United States of America
| | - May-Linh Hyunh
- Fatty Liver Foundation, Boise, Idaho, United States of America
| | - Henry E Chang
- Fatty Liver Foundation, Boise, Idaho, United States of America
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Karhan AN, Hizarcioglu-Gulsen H, Gumus E, Akçören Z, Demir H, Saltik-Temizel İN, Orhan D, Özen H. Distinctive Features of Hepatic Steatosis in Children: Is It Primary or Secondary to Inborn Errors of Metabolism? Pediatr Gastroenterol Hepatol Nutr 2021; 24:518-527. [PMID: 34796096 PMCID: PMC8593365 DOI: 10.5223/pghn.2021.24.6.518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 08/11/2021] [Accepted: 08/29/2021] [Indexed: 01/24/2023] Open
Abstract
PURPOSE The incidence of hepatic steatosis among children has been increasing; however, data distinguishing simple steatosis from a more complex disorder are lacking. METHODS This study identified the etiologies resulting in hepatic steatosis through a retrospective review of pediatric liver biopsies performed in the last 10 years. A total of 158 patients with hepatic steatosis proven by histopathological evaluation were enrolled in the study, and baseline demographic features, anthropometric measurements, physical examination findings, laboratory data, ultrasonographic findings, and liver histopathologies were noted. RESULTS The two most common diagnoses were inborn errors of metabolism (IEM) (52.5%) and nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) (29.7%). The three most common diseases in the IEM group were glycogen storage disorders, Wilson's disease, and mitochondrial disease. The rates of consanguineous marriage (75.6%; odds ratio [OR], 26.040) and positive family history (26.5%; OR, 8.115) were significantly higher (p=0.002, p<0.001, respectively) in the IEM group than those in the NAFLD/NASH group. Younger age (p=0.001), normal anthropometric measurements (p=0.03), increased aspartate aminotransferase levels (p<0.001), triglyceride levels (p=0.001), and cholestatic biochemical parameters with disrupted liver function tests, as well as severe liver destruction of hepatic architecture, cholestasis, fibrosis, and nodule formation, were also common in the IEM group. CONCLUSION Parents with consanguinity and positive family history, together with clinical and biochemical findings, may provide a high index of suspicion for IEM to distinguish primary steatosis from the consequence of a more complex disorder.
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Affiliation(s)
- Asuman Nur Karhan
- Department of Pediatrics, Division of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Hayriye Hizarcioglu-Gulsen
- Department of Pediatrics, Division of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ersin Gumus
- Department of Pediatrics, Division of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Zuhal Akçören
- Department of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Hülya Demir
- Department of Pediatrics, Division of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - İnci Nur Saltik-Temizel
- Department of Pediatrics, Division of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Diclehan Orhan
- Department of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Hasan Özen
- Department of Pediatrics, Division of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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George J, Zhang Y, Sloan J, Sims JM, Imig JD, Zhao X. Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice. Front Immunol 2021; 12:747794. [PMID: 34675931 PMCID: PMC8523998 DOI: 10.3389/fimmu.2021.747794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/16/2021] [Indexed: 11/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
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Affiliation(s)
- Jasmine George
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Yuanyuan Zhang
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Jacob Sloan
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Joya M Sims
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Xueying Zhao
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
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11
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Cataldi M, Citro V, Resnati C, Manco F, Tarantino G. New Avenues for Treatment and Prevention of Drug-Induced Steatosis and Steatohepatitis: Much More Than Antioxidants. Adv Ther 2021; 38:2094-2113. [PMID: 33761100 PMCID: PMC8107075 DOI: 10.1007/s12325-021-01669-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/11/2021] [Indexed: 12/12/2022]
Abstract
Drug-induced lipid accumulation in the liver may induce two clinically relevant conditions, drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH). The list of drugs that may cause DIS or DISH is long and heterogeneous and includes therapeutically relevant molecules that cannot be easily replaced by less hepatotoxic medicines, therefore making specific strategies necessary for DIS/DISH prevention or treatment. For years, the only available tools to achieve these goals have been antioxidant drugs and free radical scavengers, which counteract drug-induced mitochondrial dysfunction but, unfortunately, have only limited efficacy. In the present review we illustrate how in vitro preclinical research unraveled new key players in the pathogenesis of specific forms of DISH, and how, in a few cases, proof of concept of the beneficial effects of their pharmacological modulation has been obtained in vivo in animal models of this condition. The key issue emerging from these studies is that, in selected cases, liver toxicity depends on mechanisms unrelated to those responsible for the desired, primary pharmacological effects of the toxic drug and, therefore, specific strategies can be designed to overcome steatogenicity without making the drug ineffective. In particular, the hepatotoxic drug could be given in combination with a second molecule intended to selectively antagonize its liver toxicity whilst, ideally, potentiating its desired pharmacological activity. Although most of the evidence that we discuss is from in vitro or animal models and will need to be further explored and validated in humans, it highlights new avenues to be pursued in order to improve the safety of steatogenic drugs.
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Affiliation(s)
- Mauro Cataldi
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Vincenzo Citro
- Department of General Medicine, "Umberto I" Hospital, Nocera Inferiore, SA, Italy
| | - Chiara Resnati
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Federica Manco
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, "Federico II" University Medical School of Naples, Naples, Italy.
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12
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Zhu Y, Zhao H, Lu J, Lin K, Ni J, Wu G, Tang H. Caspase-11-Mediated Hepatocytic Pyroptosis Promotes the Progression of Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2021; 12:653-664. [PMID: 33894425 PMCID: PMC8261017 DOI: 10.1016/j.jcmgh.2021.04.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is an inflammatory disease with severe outcomes. Hepatocyte death, including apoptosis, necrosis, and pyroptosis, has been implicated in pathophysiology of NASH. Pyroptosis is mediated by inflammasome activation pathways including caspase-1-mediated canonical signaling pathway and caspase-11-mediated noncanonical signaling pathway. Until now, the precise role of caspase-11 in NASH remains unknown. In the present study, the potential roles of caspase-11 in NASH were explored. METHODS We established methionine- and choline-deficient diet (MCD)-induced NASH mice model using wild-type caspase-11-deficient mice. The expression of caspase-11, liver injury, fibrosis, inflammation, and activation of gasdermin D and interleukin-1β were evaluated. RESULTS Upregulated caspase-11 was detected in liver of mice with NASH. MCD-treated caspase-11-deficient mice had significantly decreased liver injury, fibrosis, and inflammation. The activation of gasdermin D and interleukin-1β was inhibited in caspase-11-deficient mice after MCD treatment. Overexpression of caspase-11 promoted steatohepatitis. CONCLUSIONS Caspase-11-mediated hepatocytic pyroptosis promotes the progression of NASH.
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Affiliation(s)
- Yingwei Zhu
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, China; Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Han Zhao
- Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jian Lu
- Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Kai Lin
- Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jingbin Ni
- Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Gaojue Wu
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, China; Department of Gastroenterology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China.
| | - Hong Tang
- Department of Pathology, Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China.
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13
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Gerges SH, Wahdan SA, Elsherbiny DA, El-Demerdash E. Non-alcoholic fatty liver disease: An overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions. Life Sci 2021; 271:119220. [PMID: 33592199 DOI: 10.1016/j.lfs.2021.119220] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder of excessive fat accumulation in the liver, known as steatosis, without alcohol overconsumption. NAFLD can either manifest as simple steatosis or steatohepatitis, known as non-alcoholic steatohepatitis (NASH), which is accompanied by inflammation and possibly fibrosis. Furthermore, NASH might progress to hepatocellular carcinoma. NAFLD and NASH prevalence is in a continuous state of growth, and by 2018, NAFLD became a devastating metabolic disease with a global pandemic prevalence. The pathophysiology of NAFLD and NASH is not fully elucidated, but is known to involve the complex interplay between different metabolic, environmental, and genetic factors. In addition, unhealthy dietary habits and pre-existing metabolic disturbances together with other risk factors predispose NAFLD development and progression from simple steatosis to steatohepatitis, and eventually to fibrosis. Despite their growing worldwide prevalence, to date, there is no FDA-approved treatment for NAFLD and NASH. Several off-label medications are used to target disease risk factors such as obesity and insulin resistance, and some medications are used for their hepatoprotective effects. Unfortunately, currently used medications are not sufficiently effective, and research is ongoing to investigate the beneficial effects of different drugs and phytochemicals in NASH. In this review article, we outline the different risk factors and pathophysiological mechanisms involved in NAFLD, diagnostic procedures, and currently used management techniques.
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Affiliation(s)
- Samar H Gerges
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt.
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14
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Inhibition of hyaluronan synthesis by 4-methylumbelliferone ameliorates non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-induced murine model. Arch Pharm Res 2021; 44:230-240. [PMID: 33486695 DOI: 10.1007/s12272-021-01309-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 01/13/2021] [Indexed: 02/07/2023]
Abstract
Hyaluronan (HA) as a glycosaminoglycan can bind to cell-surface receptors, such as TLR4, to regulate inflammation, tissue injury, repair, and fibrosis. 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, is a drug used for the treatment of biliary spasms. Currently, therapeutic interventions are not available for non-alcoholic steatohepatitis (NASH). In this study, we investigated the effects of 4-MU on NASH using a choline-deficient amino acid (CDAA) diet model. CDAA diet-fed mice showed NASH characteristics, including hepatocyte injury, hepatic steatosis, inflammation, and fibrogenesis. 4-MU treatment significantly reduced hepatic lipid contents in CDAA diet-fed mice. 4-MU reversed CDAA diet-mediated inhibition of Ppara and induction of Srebf1 and Slc27a2. Analysis of serum ALT and AST levels revealed that 4-MU treatment protected against hepatocellular damage induced by CDAA diet feeding. TLR4 regulates low molecular weight-HA-induced chemokine expression in hepatocytes. In CDAA diet-fed, 4-MU-treated mice, the upregulated chemokine/cytokine expression, such as Cxcl1, Cxcl2, and Tnf was attenuated with the decrease of macrophage infiltration into the liver. Moreover, HA inhibition repressed CDAA diet-induced mRNA expression of fibrogenic genes, Notch1, and Hes1 in the liver. In conclusion, 4-MU treatment inhibited liver steatosis and steatohepatitis in a mouse model of NASH, implicating that 4-MU may have therapeutic potential for NASH.
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15
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Roth K, Imran Z, Liu W, Petriello MC. Diet as an Exposure Source and Mediator of Per- and Polyfluoroalkyl Substance (PFAS) Toxicity. FRONTIERS IN TOXICOLOGY 2020; 2:601149. [PMID: 35296120 PMCID: PMC8915917 DOI: 10.3389/ftox.2020.601149] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/06/2020] [Indexed: 01/09/2023] Open
Abstract
Per- and polyfluoroalkyl substances (PFAS) are ubiquitously found in the environment due to their widespread commercial use and high chemical stability. Humans are exposed primarily through ingestion of contaminated water and food and epidemiological studies over the last several decades have shown that PFAS levels are associated with adverse chronic health effects, including cardiometabolic disorders such as hyperlipidemia and non-alcoholic fatty liver disease. Perhaps the most well-established effects, as demonstrated in animal studies and human epidemiological studies, are the metabolic alterations PFAS exposure can lead to, especially on lipid homeostasis and signaling. This altered lipid metabolism has often been linked to conditions such as dyslipidemia, leading to fatty liver disease and steatosis. Western diets enriched in high fat and high cholesterol containing foods may be an important human exposure route of PFAS and may also act as an important modulator of associated toxicities. In fact, the chemical structure of PFAS resemble fatty acids and may activate some of the same signaling cascades critical for endogenous metabolism. In this review we aim to outline known dietary exposure sources of PFAS, describe the detrimental metabolic health effects associated with PFAS exposure, and focus on studies examining emerging interaction of dietary effects with PFAS exposure that further alter the dysregulated metabolic state.
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Affiliation(s)
- Katherine Roth
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States
| | - Zunaira Imran
- Department of Chemistry, Wayne State University, Detroit, MI, United States
| | - Wanqing Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI, United States
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Michael C. Petriello
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
- *Correspondence: Michael C. Petriello
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16
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Virgen-Carrillo CA, Martínez Moreno AG, Rodríguez-Gudiño JJ, Pineda-Lozano JE. Feeding pattern, biochemical, anthropometric and histological effects of prolonged ad libitum access to sucrose, honey and glucose-fructose solutions in Wistar rats. Nutr Res Pract 2020; 15:187-202. [PMID: 33841723 PMCID: PMC8007410 DOI: 10.4162/nrp.2021.15.2.187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/27/2020] [Accepted: 10/14/2020] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND/OBJECTIVES The exposure to sucrose in rats has mimic abnormalities attributed to metabolic syndrome (MetS). The effects of honey bee and "free" glucose and fructose, have not been explored in this context. The aim was to expose Wistar rodents to sucrose solution (SS), honey solution (HS) and fructose/glucose solution (GFS) at 30% to assess their effects. SUBJECTS/METHODS HS (n = 10), SS (n = 10) and GFS (n = 10) groups were formed. Solutions were ad libitum along 14-weeks. RESULTS Between solutions consumptions, honey was significantly 42% higher (P = 0.000), while similar consumption was observed among GFS and SS. The feeding pattern of HS consumption was irregular along experiment; while the food intake pattern showed the similar trend among groups along time. Non statistical differences were obtained in any biochemical and anthropometric measure, however, a higher concentration of leptin (721 ± 507 pg/mL), lower concentration of total cholesterol (TC; 48.87 ± 2.41 mg/100 mL), very low density lipoprotein (VLDL; 16.47 ± 6.55 mg/100 mL) and triglycerides (82.37 ± 32.77 mg/100 mL) was obtained in SS group. For anthropometric values, HS showed less total adipose tissue (AT; average 26 vs. 31-33 g) and adiposity index (average 6.11 vs. 7.6). Due to sugar-sweetened beverages consumption increases the risk for the development of chronic diseases; correlations between fluid intake and anthropometric and biochemical parameters were assessed. A moderate correlation was obtained in groups with the weight of total AT and solution intake; for the weight gain in GFS group and for triglycerides in HS and GFS. The highest hepatic tissue damage was observed in SS group with multiple intracytoplasmic vacuoles, atypia changes, moderate pleomorphism and hepatocellular necrosis. CONCLUSIONS In spite of the significantly higher consumption of HS, biochemical, anthropometrical and histological effects were not remarkably different in comparision to other sweeteners.
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Affiliation(s)
- Carmen Alejandrina Virgen-Carrillo
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Z.C. 49000, City Guzmán, Municipio de Zapotlán el Grande, Jalisco, México
| | - Alma Gabriela Martínez Moreno
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Z.C. 49000, City Guzmán, Municipio de Zapotlán el Grande, Jalisco, México
| | - Juan José Rodríguez-Gudiño
- Laboratorio de Morfología, Sección de Histopatología, Centro Universitario del Sur, Universidad de Guadalajara, Z.C. 49000, City Guzmán, Municipio de Zapotlán el Grande, Jalisco, México
| | - Jessica Elizabeth Pineda-Lozano
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Z.C. 49000, City Guzmán, Municipio de Zapotlán el Grande, Jalisco, México
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17
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Hyun J, Jung Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:8138. [PMID: 33143364 PMCID: PMC7662478 DOI: 10.3390/ijms21218138] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 10/28/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a widespread hepatic disorder in the United States and other Westernized countries. Nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD, can progress to end-stage liver disease, including cirrhosis and liver cancer. Poor understanding of mechanisms underlying NAFLD progression from simple steatosis to NASH has limited the development of effective therapies and biomarkers. An accumulating body of studies has suggested the importance of DNA methylation, which plays pivotal roles in NAFLD pathogenesis. DNA methylation signatures that can affect gene expression are influenced by environmental and lifestyle experiences such as diet, obesity, and physical activity and are reversible. Hence, DNA methylation signatures and modifiers in NAFLD may provide the basis for developing biomarkers indicating the onset and progression of NAFLD and therapeutics for NAFLD. Herein, we review an update on the recent findings in DNA methylation signatures and their roles in the pathogenesis of NAFLD and broaden people's perspectives on potential DNA methylation-related treatments and biomarkers for NAFLD.
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Affiliation(s)
- Jeongeun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
- Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 31116, Korea
- Cell and Matter Institute, Dankook University, Cheonan 31116, Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea
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18
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Vesković M, Labudović-Borović M, Mladenović D, Jadžić J, Jorgačević B, Vukićević D, Vučević D, Radosavljević T. Effect of Betaine Supplementation on Liver Tissue and Ultrastructural Changes in Methionine-Choline-Deficient Diet-Induced NAFLD. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2020; 26:997-1006. [PMID: 32782033 DOI: 10.1017/s1431927620024265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a hepatic manifestation of metabolic syndrome. The aim of this study was to examine the effect of betaine on ultrastructural changes in the mouse liver with methionine- and choline-deficient (MCD) diet-induced NAFLD. Male C57BL/6 mice were divided into groups: Control-fed with standard chow, BET-standard chow supplemented with betaine (1.5% w/v drinking water), MCD-fed with MCD diet, and MCD + BET-MCD diet with betaine supplementation for 6 weeks. Liver samples were taken for pathohistology and transmission electron microscopy. The MCD diet-induced steatosis, inflammation, and balloon-altered hepatocytes were alleviated by betaine. MCD diet induced an increase in mitochondrial size versus the control group (p < 0.01), which was decreased in the betaine-treated group. In the MCD diet-fed group, the total mitochondrial count decreased versus the control group (p < 0.01), while it increased in the MCD + BET group versus MCD (p < 0.01). Electron microscopy showed an increase in the number of autophagosomes in the MCD and MCD + BET group versus control, and a significant difference in autophagosomes number was detected in the MCD + BET group by comparison with the MCD diet-treated group (p < 0.05). Betaine decreases the number of enlarged mitochondria, alleviates steatosis, and increases the number of autophagosomes in the liver of mice with NAFLD.
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Affiliation(s)
- Milena Vesković
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
| | - Milica Labudović-Borović
- Institute of Histology and Embryology, Faculty of Medicine, University of Belgrade, Belgrade11000, Serbia
| | - Dušan Mladenović
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
| | - Jelena Jadžić
- Institute of Anatomy, Faculty of Medicine, University of Belgrade, Belgrade11000, Serbia
| | - Bojan Jorgačević
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
| | - Dušan Vukićević
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
| | - Danijela Vučević
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
| | - Tatjana Radosavljević
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade11000, Serbia
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Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor. JHEP Rep 2020; 2:100179. [PMID: 33134908 PMCID: PMC7588854 DOI: 10.1016/j.jhepr.2020.100179] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/28/2020] [Accepted: 08/18/2020] [Indexed: 01/08/2023] Open
Abstract
Background & Aims The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis. Methods As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption. Results Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1. Conclusions The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease. Lay summary The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.
Liver-specific knockdown of miR-192-3p recapitulated functional loss of the miRNA as in mice with diabetes. This knockdown was characterised by pronounced hepatic micro-vesicular steatosis coupled to insulin resistance. In vivo overexpression of miR-192-3p alleviated hepatic steatosis in mice with diabetes and wild-type mice with excessive fructose consumption. Glucocorticoid receptor (also known as NR3C1) was discovered as the immediate target of miR-192-3p in regulating hepatic lipid turnover and storage.
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Key Words
- 3′-UTR, 3′-untranslated region
- AAV, adeno-associated virus
- CPT, carnitine palmitoyl transferase
- DEG, differentially expressed gene
- DEX, dexamethasone
- DM, diabetes mellitus
- DNL, de novo lipogenesis
- Diabetes mellitus
- FA, fatty acid
- FAO, fatty acid oxidation
- FASN, fatty acid synthase
- GCR, glucocorticoid receptor
- Glucocorticoid receptor
- HFD, high-fat diet
- HFrD, high-fructose drink
- HOMA-IR, homeostatic model assessment of insulin resistance
- Hepatic steatosis
- High carbohydrate consumption
- MicroRNA
- NAFLD, non-alcoholic fatty liver disease
- NR3C1, nuclear receptor subfamily 3, group C, member 1
- NT, non-targeting
- OA, oleic acid
- OGTT, oral glucose tolerance test
- SCD1, stearoyl-CoA desaturase-1
- T2DM, type 2 diabetes mellitus
- TAG, triacylglyceride/triglyceride
- Transcription repressor
- VAT, visceral adipose tissue
- miRNA, microRNA
- shRNA, short hairpin RNA
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Kumar A, Shalimar, Walia GK, Gupta V, Sachdeva MP. Genetics of nonalcoholic fatty liver disease in Asian populations. J Genet 2019. [DOI: 10.1007/s12041-019-1071-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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21
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Zhang ZT, Qi WX, Liu CX, Yin SW, Zhao Y, Li-Ling J, Lv Y. A small supernumerary marker chromosome resulting in mosaic partial tetrasomy 4q26-q31.21 in a foetus with multiple congenital malformations. J Genet 2019; 98:22. [PMID: 30945692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
A parental diagnosis was performed for an unborn foetus of a healthy couple, who was due for ultrasound detection of multiple malformations and abnormal amniotic fluid karyotypes. For an accurate diagnosis, routine G-banding analysis and next generation sequencing (NGS) were carried out. Finally, conventional cytogenetic analysis suggested that the foetus had a karyotype of47,XX,+mar[52]/46,XN, meanwhile NGS also revealed a partial tetrasomy of 27.84Mb from 4q26-q31.21 (117,385,735-145,225,759), and G-banding analysis excluded the couple to have carried the 4q26-q31.21 duplication. We have identified a de novo mosaic small supernumerary marker chromosomes (sSMC) derived from 4q26-q31.21 in a foetus with hemivertebra, polydactyly, abnormal ears, and heart and ventricular septal defect.
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Affiliation(s)
- Zhi-Tao Zhang
- Liaoning Centre for Prenatal Diagnosis, Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, People's Republic of China.
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Changes of the Fatty Acid Profile in Erythrocyte Membranes of Patients following 6-Month Dietary Intervention Aimed at the Regression of Nonalcoholic Fatty Liver Disease (NAFLD). Can J Gastroenterol Hepatol 2018; 2018:5856201. [PMID: 30631760 PMCID: PMC6304595 DOI: 10.1155/2018/5856201] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/16/2018] [Accepted: 11/22/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is closely related to the metabolism disorders of fatty acids. The pathogenesis of the disease includes an increased concentration of FFA in blood, an increase in the biosynthesis of fatty acids, and disorders in the process of β-oxidation. OBJECTIVE The aim of the study was to analyze the fatty acids in erythrocyte membranes among 55 patients with NAFLD who were subjected to a 6-month dietary intervention in order to reduce fatty liver. MATERIALS AND METHODS Basic anthropometric and biochemical measurements were performed. The profile of fatty acids was measured in the membranes of erythrocytes and analyzed by gas chromatography. The dietary compliance was evaluated using 72-diary questionnaires, anthropometric measurements. RESULTS With the reduction of fatty liver (p<0.01), the patients' biochemical and anthropometric parameters were significantly improved. A significant decrease in the concentration of alanine aminotransferase (p<0.01) and asparagine aminotransferase (p<0.01) was observed, along with a decrease in the amount of insulin (p<0.05) and insulin resistance (p<0.05). Significant changes in terms of the fatty acid profile were observed among patients who followed the dietary intervention. There was a noticeable tendency in terms of the reduction palmitic acid (p<0.055) and a significant reduction of stearic acid (p<0.05). Significant changes in the profile of fatty acids were also associated with the reductionof palmitoleic (p<0.05) and oleic acids (p<0.05). Another statistically significant change observed was the increase in polyunsaturated fatty acids. In particular (p<0.01) the rise of eicosapentaenoic (p<0.055) and docosahexaenoic acids (p<0.55) was noted. CONCLUSION The profile of fatty acids turned out to be a potential biomarker of the liver changes during NAFLD regression. Further research is needed to fully elucidate the usefulness and applicability of our findings in the management of NAFLD.
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Spradley FT, Smith JA, Alexander BT, Anderson CD. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab 2018; 315:E795-E814. [PMID: 29509436 PMCID: PMC6293166 DOI: 10.1152/ajpendo.00394.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and nonalcoholic fatty liver disease (NAFLD). It is unclear whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled type 2 diabetes mellitus, which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those proinflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD.
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Affiliation(s)
- Frank T Spradley
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Jillian A Smith
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Barbara T Alexander
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
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von Loeffelholz C, Horn P, Birkenfeld AL, Claus RA, Metzing BU, Döcke S, Jahreis G, Heller R, Hoppe S, Stockmann M, Lock JF, Rieger A, Weickert MO, Settmacher U, Rauchfuß F, Pfeiffer AFH, Bauer M, Sponholz C. Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease. J INVEST SURG 2016; 29:266-274. [PMID: 26980291 DOI: 10.3109/08941939.2016.1149640] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. OBJECTIVE To study fetuin A as predictor of NAFLD/NASH in preoperative patients. METHODS 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. RESULTS Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. CONCLUSION Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.
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Affiliation(s)
- C von Loeffelholz
- a Department of Clinical Nutrition , German Institute of Human Nutrition Potsdam-Rehbruecke , Nuthetal , Germany
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
| | - P Horn
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
| | - A L Birkenfeld
- d Section of Metabolic and Vascular Medicine, Medical Clinic III , University Hospital Carl Gustav Carus , Dresden , Germany
| | - R A Claus
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
| | - B U Metzing
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
| | - S Döcke
- a Department of Clinical Nutrition , German Institute of Human Nutrition Potsdam-Rehbruecke , Nuthetal , Germany
| | - G Jahreis
- e Institute of Nutrition , Friedrich Schiller University , Jena , Germany
| | - R Heller
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- f Institute for Molecular Cell Biology , Germany Center for Molecular Biomedicine, Jena University Hospital , Jena , Germany
| | - S Hoppe
- g Department of General, Visceral and Transplantation Surgery , Charité-Universitätsmedizin , Berlin , Germany
| | - M Stockmann
- g Department of General, Visceral and Transplantation Surgery , Charité-Universitätsmedizin , Berlin , Germany
| | - J F Lock
- h Department of General-, Visceral-, Vascular- and Paediatric Surgery , University Hospital of Wuerzburg , Wuerzburg , Germany
| | - A Rieger
- i Institute of Pathology , Charité-Universitätsmedizin , Berlin , Germany
| | - M O Weickert
- j Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism , University Hospitals Coventry and Warwickshire , CV2 2DX , Coventry , UK , Division of Metabolic & Vascular Health , University of Warwick , CV4 7AL , Coventry , UK
| | - U Settmacher
- k Department of General, Visceral and Transplantation Surgery , Friedrich Schiller University of Jena , Jena , Germany
| | - F Rauchfuß
- k Department of General, Visceral and Transplantation Surgery , Friedrich Schiller University of Jena , Jena , Germany
| | - A F H Pfeiffer
- a Department of Clinical Nutrition , German Institute of Human Nutrition Potsdam-Rehbruecke , Nuthetal , Germany
- l Department of Endocrinology, Diabetes, and Nutrition , Charité-Universitätsmedizin , Berlin , Germany
| | - M Bauer
- b Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) , Friedrich Schiller University , Jena , Germany
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
| | - C Sponholz
- c Department of Anaesthesiology and Intensive Care , Jena University Hospital , Jena , Germany
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Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids 2016; 197:3-12. [DOI: 10.1016/j.chemphyslip.2015.08.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 08/27/2015] [Accepted: 08/31/2015] [Indexed: 01/07/2023]
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Grandone A, Cozzolino D, Marzuillo P, Cirillo G, Di Sessa A, Ruggiero L, Di Palma MR, Perrone L, Miraglia Del Giudice E. TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatr Obes 2016; 11:115-119. [PMID: 25893821 DOI: 10.1111/ijpo.12032] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. OBJECTIVES The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. METHODS We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. RESULTS The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. CONCLUSION Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health.
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Affiliation(s)
- A Grandone
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - D Cozzolino
- Division of Internal Medicine, Seconda Università di Napoli, Napoli, Italy
| | - P Marzuillo
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - G Cirillo
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - A Di Sessa
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - L Ruggiero
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - M R Di Palma
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - L Perrone
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
| | - E Miraglia Del Giudice
- Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, Italy
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Li L, Xie W, Zheng XL, Yin WD, Tang CK. A novel peptide adropin in cardiovascular diseases. Clin Chim Acta 2016; 453:107-13. [DOI: 10.1016/j.cca.2015.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/05/2015] [Accepted: 12/08/2015] [Indexed: 12/16/2022]
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Fujio A, Kawagishi N, Echizenya T, Tokodai K, Nakanishi C, Miyagi S, Sato K, Fujimori K, Ohuchi N. Long-term survival with growth hormone replacement after liver transplantation of pediatric nonalcoholic steatohepatitis complicating acquired hypopituitarism. TOHOKU J EXP MED 2015; 235:61-7. [PMID: 25744617 DOI: 10.1620/tjem.235.61] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD). In adult patients, liver transplantation (LT) is the treatment of choice for end-stage liver disease secondary to NASH. However, little information is available regarding outcomes of LT in pediatric patients with NASH. We describe here a pediatric patient with NASH associated with hypopituitarism who underwent living donor liver transplantation (LDLT). An 11-year-old boy was diagnosed with a pituitary tumor, which was removed by trans-interhemispheric approach following bifrontal craniotomy. Histopathological examination revealed a mature teratoma. Eighteen months later, magnetic resonance imaging showed recurrence of the pituitary tumor, which was found to be a germinoma. He underwent 3 months of chemoradiotherapy, with a complete response. He gradually became obese, with elevated transaminase levels. At age 15 years, he developed fatigue and dyspnea and was found to have liver cirrhosis secondary to NASH with severe hepatopulmonary syndrome. He underwent LDLT using a right liver graft from his mother. Twelve months later, abdominal computed tomography showed recurrence of NAFLD. Five years after the LDLT, transaminases were slightly elevated. Growth hormone replacement therapy was started, reducing transaminase levels to their normal ranges. Ten years after LDLT, fatty liver remains stable, although his body mass index has not been reduced. Growth hormone replacement therapy may be effective in graft maintenance. This is the first case report of a patient with maintained stable liver function 10 years after LDLT for pediatric NASH.
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Affiliation(s)
- Atsushi Fujio
- Division of Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University Hospital
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Kocaoglu C, Buyukinan M, Erdem SS, Ozel A. Are obesity and metabolic syndrome associated with plasma adropin levels in children? J Pediatr Endocrinol Metab 2015. [PMID: 26226125 DOI: 10.1515/jpem-2015-0117] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Studies performed on mice suggest that adropin is a peptide hormone playing a role in metabolic homeostasis and prevention of obesity-associated insulin resistance. Our study was conducted to investigate the role of adropin in children with obesity or metabolic syndrome. The study group consisted of 70 patients, including 42 obese and 28 with metabolic syndrome, and 26 healthy volunteers. After anthropometric variables and blood pressure of all participants were measured, serum lipids were analyzed, liver USG and oral glucose tolerance test were performed, and HOMA-IR values were calculated. Plasma adropin levels were collectively analyzed from collected plasma samples. In patient and control groups, no difference was observed in the levels of adropin (327.7±124.7 vs. 344.6±208.5 ng/L, respectively). The adropin levels of metabolic syndrome, obesity, and control groups also showed no difference (316±142.3, 335.8±112.5, and 344.6±208.5 ng/L, respectively). While the adropin levels of patients with and without hepatic steatosis were 319.6±123.7 and 347.8±128.7 ng/L, respectively, patients with HOMA-IR values of <3.16 and ≥3.16 had levels 342.3±124.8 and 296.5±136.7 ng/L, respectively. Although statistically insignificant, our findings are considered to support the hypothesis suggesting a nexus between adropin and obesity and metabolic syndrome. Small sample size in our study may have prevented our results to reach a more significant level. So, long-term follow-up studies with large population are needed to enlighten the role of adropin in metabolic homeostasis.
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Delvin E, Patey N, Dubois J, Henderson M, Lévy É. Pediatric Non-Alcoholic Fatty Liver Disease. J Med Biochem 2015; 34:3-12. [PMID: 28356817 PMCID: PMC4922334 DOI: 10.2478/jomb-2014-0059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The rapidly increasing prevalence of childhood obesity and its associated co-morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis.
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Affiliation(s)
- Edgard Delvin
- Departement of Biochemistry, University of Montreal, Montreal, Quebec, Canada
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
| | - Natasha Patey
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
- Department of Pathology, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
- Department of Cell Biology and Pathology, University of Montreal, Montreal, Quebec, Canada
| | - Josée Dubois
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
- Department of Radiology, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Melanie Henderson
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
- Divisions of Genetics and Endocrinology, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
| | - Émile Lévy
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
- Department of Nutrition, University of Montreal, Montreal, Quebec, Canada
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Middleton JP, Wiener RC, Barnes BH, Gurka MJ, DeBoer MD. Clinical features of pediatric nonalcoholic fatty liver disease: a need for increased awareness and a consensus for screening. Clin Pediatr (Phila) 2014; 53:1318-25. [PMID: 24477713 PMCID: PMC4450252 DOI: 10.1177/0009922813520072] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Jeremy P. Middleton
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Virginia, Charlottesville, VA
| | | | - Barrett H. Barnes
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Virginia, Charlottesville, VA
| | - Matthew J. Gurka
- Department of Biostatistics, School of Public Health, West Virginia University, Morgantown, WV, USA
| | - Mark D. DeBoer
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA
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Al-Eryani L, Wahlang B, Falkner KC, Guardiola JJ, Clair HB, Prough RA, Cave M. Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents. Toxicol Pathol 2014; 43:482-97. [PMID: 25326588 DOI: 10.1177/0192623314549960] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Toxicant-associated fatty liver disease (TAFLD) is a recently identified form of nonalcoholic fatty liver disease (NAFLD) associated with exposure to industrial chemicals and environmental pollutants. Numerous studies have been conducted to test the association between industrial chemicals/environmental pollutants and fatty liver disease both in vivo and in vitro. OBJECTIVES The objective of the article is to report a list of chemicals associated with TAFLD. METHODS Two federal databases of rodent toxicology studies-Toxicological Reference Database (ToxRefDB; Environmental Protection Agency) and Chemical Effects in Biological Systems (CEBS, National Toxicology Program)-were searched for liver end points. Combined, these 2 databases archive nearly 2,000 rodent studies. Toxicant-associated steatohepatitis (TASH) descriptors including fatty change, fatty necrosis, Oil red O-positive staining, steatosis, and lipid deposition were queried. RESULTS Using these search terms, 123 chemicals associated with fatty liver were identified. Pesticides and solvents were the most frequently identified chemicals, while polychlorinated biphenyls (PCBs)/dioxins were the most potent. About 44% of identified compounds were pesticides or their intermediates, and >10% of pesticide registration studies in ToxRefDB were associated with fatty liver. Fungicides and herbicides were more frequently associated with fatty liver than insecticides. CONCLUSION More research on pesticides, solvents, metals, and PCBs/dioxins in NAFLD/TAFLD is warranted due to their association with liver damage.
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Affiliation(s)
- Laila Al-Eryani
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Banrida Wahlang
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - K C Falkner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - J J Guardiola
- University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - H B Clair
- University of Louisville School of Medicine, Louisville, Kentucky, USA Department of Biochemistry & Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - R A Prough
- Department of Biochemistry & Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Matt Cave
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA University of Louisville School of Medicine, Louisville, Kentucky, USA Department of Biochemistry & Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA Robley Rex Louisville VAMC, Louisville, Kentucky, USA
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Marzuillo P, Miraglia del Giudice E, Santoro N. Pediatric fatty liver disease: role of ethnicity and genetics. World J Gastroenterol 2014; 20:7347-7355. [PMID: 24966605 PMCID: PMC4064080 DOI: 10.3748/wjg.v20.i23.7347] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 01/04/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs' group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.
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Steatosis and steatohepatitis: complex disorders. Int J Mol Sci 2014; 15:9924-44. [PMID: 24897026 PMCID: PMC4100130 DOI: 10.3390/ijms15069924] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/01/2014] [Accepted: 05/20/2014] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) which includes steatosis and steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), is a rising health problem world-wide and should be separated from alcoholic steatohepatitis (ASH). NAFLD is regarded as hepatic manifestation of the metabolic syndrome (MetSy), being tightly linked to obesity and type 2 diabetes mellitus (T2DM). Development of steatosis, liver fibrosis and cirrhosis often progresses towards hepatocellular carcinogenesis and frequently results in the indication for liver transplantation, underlining the clinical significance of this disease complex. Work on different murine models and several human patients studies led to the identification of different molecular key players as well as epigenetic factors like miRNAs and SNPs, which have a promoting or protecting function in AFLD/ASH or NAFLD/NASH. To which extent they might be translated into human biology and pathogenesis is still questionable and needs further investigation regarding diagnostic parameters, drug development and a better understanding of the genetic impact. In this review we give an overview about the currently available knowledge and recent findings regarding the development and progression of this disease.
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Sayın O, Tokgöz Y, Arslan N. Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease. J Pediatr Endocrinol Metab 2014; 27:479-484. [PMID: 24468600 DOI: 10.1515/jpem-2013-0296] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 12/16/2013] [Indexed: 11/15/2022]
Abstract
AIM Nonalcoholic fatty liver disease (NAFLD) is the accumulation of excess fat in the liver in the absence of alcohol consumption, which is commonly associated with obesity and increased risk of atherosclerosis as well as insulin resistance. Adropin is a recently identified protein encoded by the gene related with energy homeostasis, which is expressed in the liver and the brain and has a role in preventing insulin resistance and obesity. The aim of this study was to investigate the serum adropin and leptin levels in obese adolescents and compare the patients with, and without, NAFLD and with healthy controls. METHODS Sixty-four obese adolescents (30 with NAFLD, 34 without NAFLD) and 36 healthy controls were enrolled in the study. Serum adropin and leptin levels were evaluated by sandwich enzyme-linked immunosorbent assay. RESULTS Serum adropin levels were significantly lower in obese children than healthy controls (3.2±1.0 and 9.2±1.2 ng/mL, respectively, p=0.001). Serum leptin levels were significantly higher in patients than in controls (12.4±1.1 and 4.1±3.1 pg/mL, respectively; p=0.000). Serum adropin levels of patients with NAFLD were significantly lower than in patients without NAFLD (2.9±0.5 and 3.5±1.2 ng/mL, respectively; p=0.023) and healthy controls (p=0.000). Logistic regression analysis showed that a decrease in adropin levels was the only independent factor for fatty liver disease in obese adolescents (odds ratio: 3.07, 95% confidence interval 1.14-8.2, p=0.026). Leptin, relative weight and HOMA-IR of the patients were not independent risk factors for NAFLD. CONCLUSIONS In this study, serum adropin levels were significantly lower in obese adolescents with fatty liver disease compared to patients without fatty liver disease and healthy controls. Lower adropin level was an independent risk factor for NAFLD in obese adolescents in logistic regression analysis. Assessment of serum adropin concentrations may provide a reliable indicator of fatty liver disease in obese adolescents.
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Marzuillo P, Del Giudice EM, Santoro N. Pediatric non-alcoholic fatty liver disease: New insights and future directions. World J Hepatol 2014; 6:217-225. [PMID: 24799990 PMCID: PMC4009477 DOI: 10.4254/wjh.v6.i4.217] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 02/25/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.
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Affiliation(s)
- Pierluigi Marzuillo
- Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Department of women and children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Department of women and children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy
| | - Nicola Santoro
- Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Department of women and children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy
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Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma. J Gastrointest Surg 2013; 17:748-55. [PMID: 23355033 PMCID: PMC4007003 DOI: 10.1007/s11605-013-2149-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Accepted: 01/16/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. METHODS Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. RESULTS Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m(2), p < 0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p = 0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p = 0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p < 0.001). Macrovascular (35.5 vs. 11.3 %, p = 0.01) and any vascular (48.4 vs. 26.7 %, p = 0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p = 0.42) or overall (median, 31.5 versus 36.3 months, p = 0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. CONCLUSIONS Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma.
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Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr 2013; 13:40. [PMID: 23530957 PMCID: PMC3620555 DOI: 10.1186/1471-2431-13-40] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/18/2013] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives.
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Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, Cave MC. Toxicant-associated steatohepatitis. Toxicol Pathol 2013; 41:343-60. [PMID: 23262638 PMCID: PMC5114851 DOI: 10.1177/0192623312468517] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.
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Affiliation(s)
- Banrida Wahlang
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Juliane I. Beier
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather B. Clair
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather J. Bellis-Jones
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - K. Cameron Falkner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Craig J. McClain
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
| | - Matt C. Cave
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
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Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci 2013; 1281:106-22. [PMID: 23363012 PMCID: PMC3646408 DOI: 10.1111/nyas.12016] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ∼5% is believed to improve steatosis, whereas ∼10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.
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Affiliation(s)
- Howard C Masuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Hardwick RN, Cherrington NJ. Measuring altered disposition of xenobiotics in experimental models of liver disease. ACTA ACUST UNITED AC 2012; Chapter 23:Unit 23.1.. [PMID: 22549269 DOI: 10.1002/0471140856.tx2301s52] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Understanding the metabolic pathway and excretion mechanisms governing the disposition of a compound is essential to the safe use of pharmaceutical agents. Because the liver is the primary organ responsible for the metabolism and elimination of xenobiotics, chronic liver disease can have a significant effect on the disposition of many xenobiotics due to changes in the expression or function of drug metabolizing enzymes and transporters. Liver disease can result in increased retention of a xenobiotic within the body, causing greater exposure of the individual to a potentially harmful compound, which may lead to toxicity. On the other hand, liver disease may also up-regulate the elimination processes of a xenobiotic, accelerating its removal from the body. With regard to a pharmaceutical agent, enhanced elimination may result in a decreased pharmacologic effect. Such alterations may necessitate dosage adjustments to achieve the desired therapeutic outcome.
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Affiliation(s)
- Rhiannon N Hardwick
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA
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Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, Humar A, Marsh JW, Geller DA, Tsung A. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012; 55:1809-19. [PMID: 22183968 DOI: 10.1002/hep.25536] [Citation(s) in RCA: 184] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2011] [Accepted: 12/06/2011] [Indexed: 12/11/2022]
Abstract
UNLABELLED Concomitant increasing incidences of hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from NASH. The aim of this study was to determine differences in severity of liver dysfunction at HCC diagnosis and long-term survival outcomes between patients undergoing curative therapy for HCC in the background of NASH compared to hepatitis C virus (HCV) and/or alcoholic liver disease (ALD). Patient demographics and comorbidities, clinicopathologic data, and long-term outcomes among patients who underwent liver transplantation, hepatic resection, or radiofrequency ablation for HCC were reviewed. From 2000 to 2010, 303 patients underwent curative treatment of HCC; 52 (17.2%) and 162 (53.5%) patients had NASH and HCV and/or alcoholic liver disease. At HCC diagnosis, NASH patients were older (median age 65 versus 58 years), were more often female (48.1% versus 16.7%), more often had the metabolic syndrome (45.1% versus 14.8%), and had lower model for end-stage liver disease scores (median 9 versus 10) (all P < 0.05). NASH patients were less likely to have hepatic bridging fibrosis or cirrhosis (73.1% versus 93.8%; P < 0.001). After a median follow-up of 50 months after curative treatment, the most frequent cause of death was liver failure. Though there were no differences in recurrence-free survival after curative therapy (median, 60 versus 56 months; P = 0.303), NASH patients had longer overall survival (OS) (median not reached versus 52 months; P = 0.009) independent of other clinicopathologic factors and type of curative treatment. CONCLUSION Patients with HCC in the setting of NASH have less severe liver dysfunction at HCC diagnosis and better OS after curative treatment compared to counterparts with HCV and/or alcoholic liver disease.
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Affiliation(s)
- Srinevas K Reddy
- Departments of Surgery, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Alisi A, Nobili V. Non-alcoholic fatty liver disease in children now: lifestyle changes and pharmacologic treatments. Nutrition 2012; 28:722-6. [PMID: 22464551 DOI: 10.1016/j.nut.2011.11.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 11/13/2011] [Accepted: 11/15/2011] [Indexed: 12/31/2022]
Abstract
Over the past decade, non-alcoholic fatty liver disease (NAFLD) has become one of most common chronic liver diseases in children. A greater understanding about the risk factors and molecular pathogenesis of NAFLD suggests that lifestyle interventions aiming to decrease obesity/body mass index and metabolic derangement are the first line of treatments adopted in children affected by this disease. However, because these therapeutic options are often at the beginning misjudged by the patients and their parents, the use of pharmacologic agents may help to protect the liver and other organs from further irreversible tissue damage. Pharmacologic therapies against one or more specific factors and/or molecules involved in the development of NAFLD (i.e., insulin resistance, free fatty acid lipid toxicity, and oxidative stress) also might slow the progression of this increasingly prevalent pediatric disorder. On this basis, insulin sensitizers, antioxidants, cytoprotective agents, and dietary supplementations have been evaluated in pediatric clinical trials. In this review, we discuss the efficacy of the dietary approaches, possibly coupled with regular exercise, on decreasing the metabolic and histologic damage in pediatric NAFLD. We also emphasize several advantages of the pharmacologic treatments adopted or adoptable in combination with lifestyle interventions in children with NAFLD.
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Affiliation(s)
- Anna Alisi
- Unit of Liver Research, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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Abate N. Adipocyte maturation arrest: a determinant of systemic insulin resistance to glucose disposal. J Clin Endocrinol Metab 2012; 97:760-3. [PMID: 22392952 PMCID: PMC3319217 DOI: 10.1210/jc.2012-1140] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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