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Yang B, Cheng L, Li Y, Liu Z, Zhou C, Zhou T, Zhao Y, Du H, Liao Z, Xu A. Moderate static magnetic field modulated lipid metabolism abnormalities induced by continuous artificial light in Caenorhabditis elegans: Role of iron ions. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 292:117959. [PMID: 40022825 DOI: 10.1016/j.ecoenv.2025.117959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 11/17/2024] [Accepted: 02/22/2025] [Indexed: 03/04/2025]
Abstract
Excessive use of artificial light sources has led to a significant increase in light pollution, which has raised serious concerns due to its serious adverse effects on lipid metabolism. Although moderate static magnetic fields (SMFs) have shown potential in health intervention and treatment as non-invasive and highly permeable physical field, the influence of SMFs on lipid metabolic disturbance induced by lights remains largely unknown. In this study, we explored the lipid metabolism of Caenorhabditis elegans (C. elegans) under varying wavelengths of light ranging from 395 nm to 635 nm, both in the presence and absence of a 0.5 T SMF, and elucidated their underlying mechanisms. Exposure of C. elegans to artificial light at 200 lux resulted in a shortened lifespan while significantly increasing fat accumulation in a wavelength-dependent manner. The presence of 0.5 T SMF significantly extended the lifespan and reduced the size of fat droplets, as well as the content of triglyceride in light exposed worms. These effects were achieved by upregulating the expression of genes related to lipolysis and downregulating the expression of genes related to lipid synthesis. Moreover, the 0.5 T SMF alleviated abnormalities in lipid metabolism caused by light through the regulation of iron ions. Our findings provided clear evidence that moderate SMFs have significant protective effects on lipid metabolism abnormalities induced by artificial light via mediating iron homeostasis, which might contribute to a better understanding of the combined photomagnetic effects in living organisms.
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Affiliation(s)
- Baolin Yang
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Lei Cheng
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Yang Li
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Zicheng Liu
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Chenxi Zhou
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Tong Zhou
- Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Yanan Zhao
- Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Hua Du
- Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China
| | - Zhongcai Liao
- Heye Health Technology Co., Ltd., Huzhou 313300, PR China
| | - An Xu
- School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei 230026, PR China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, CAS, Hefei Institutes of Physical Science, CAS, Hefei, Anhui 230031, PR China.
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Wen W, Huang SM, Zhang B. Mechanisms Underlying Obesity-induced Aβ Accumulation in Alzheimer's Disease: A Qualitative Review. J Integr Neurosci 2024; 23:163. [PMID: 39344225 DOI: 10.31083/j.jin2309163] [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: 01/16/2024] [Revised: 02/27/2024] [Accepted: 03/05/2024] [Indexed: 10/01/2024] Open
Abstract
Epidemiological studies show that individuals with obesity are more likely to develop Alzheimer's disease (AD) than those who do not have obesity. However, the mechanisms underlying the relationship between obesity and AD are not entirely unclear. Here, we have reviewed and analyzed relevant articles published in the literature and found that obesity has correlation or potential increase in the levels of β-amyloid (Aβ) protein, which may explain why people with obesity are more likely to suffer from AD. Additionally, the published findings point to the roles of obesity-related metabolic disorders, such as diabetes, inflammation, oxidative stress, and imbalance in gut microbiota in Aβ accumulation caused by obesity. Therefore, in-depth experimental and clinical studies on these mechanisms in the future may help shed light on appropriate prevention and treatment strategies for AD, such as dietary changes and regular exercise to reverse or prevent obesity and related metabolic disorders.
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Affiliation(s)
- Wei Wen
- Department of Pharmacology, College of Basic Medicine, Heilongjiang University of Chinese Medicine, 150040 Harbin, Heilongjiang, China
| | - Shu-Ming Huang
- Department of Neuroscience, Institute of Chinese Medicine, Heilongjiang University of Chinese Medicine, 150040 Harbin, Heilongjiang, China
| | - Bo Zhang
- Department of Neuroscience, Institute of Chinese Medicine, Heilongjiang University of Chinese Medicine, 150040 Harbin, Heilongjiang, China
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Parsi A, Hajiani E, Sadani S, Hashemi SJ, Seyedian SS, Alimadadi M, Ghanbari R. Liver Fibrosis and Cirrhosis in Patients with Non-alcoholic Fatty Liver with and without History of Cholecystectomy: A Pilot Study. Middle East J Dig Dis 2024; 16:34-38. [PMID: 39050095 PMCID: PMC11264833 DOI: 10.34172/mejdd.2024.366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 11/09/2023] [Indexed: 07/27/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. Previous studies revealed that cholecystectomy may be considered a risk factor for the development of NAFLD. The aim of this study was to compare the amount of liver fibrosis, determined by elastography, between patients with NAFLD with and without a history of cholecystectomy. Methods In this descriptive-analytical cross-sectional study, 50 patients with NAFLD were divided into two groups: one with a history of cholecystectomy and the other without. No significant differences were found between these two groups in terms of age or sex distribution. Liver fibrosis was measured for all patients using an elastography imaging system. Subsequently, the data related to liver fibrosis, along with the demographic information of the patients, were statistically analyzed using SPSS software version 22. Results The mean elastography score in all patients was 10.66±12.18 kPa (the elasticity scale ranging from 3.80 to 66.40 kPa). The group with a history of cholecystectomy had a significantly higher mean elastography score (13.39±16.20 kPa) compared with the group without cholecystectomy (7.93±4.99 kPa) (P=0.02). Additionally, there was a significant positive correlation between body mass index (BMI) and the mean elastography score in the group of patients with a history of cholecystectomy. Conclusion The mean elastography score of patients with NAFLD with a history of cholecystectomy was approximately twice as high as that of non-cholecystectomy patients.
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Affiliation(s)
- Abazar Parsi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Eskandar Hajiani
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Somayeh Sadani
- Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seid Jalal Hashemi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seid Saeed Seyedian
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Alimadadi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Ghanbari
- Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik MA. Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma. iScience 2023; 26:108363. [PMID: 38034347 PMCID: PMC10682354 DOI: 10.1016/j.isci.2023.108363] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023] Open
Abstract
Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
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Affiliation(s)
- Alfredo Smiriglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marina Serra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
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Lempesis IG, Georgakopoulou VE. Physiopathological mechanisms related to inflammation in obesity and type 2 diabetes mellitus. World J Exp Med 2023; 13:7-16. [PMID: 37396883 PMCID: PMC10308320 DOI: 10.5493/wjem.v13.i3.7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/15/2023] [Accepted: 04/10/2023] [Indexed: 06/16/2023] Open
Abstract
Overweight, obesity, and type 2 diabetes mellitus pose global health problems that are ever-increasing. A chronic low-grade inflammatory status and the presence of various pro-inflammatory markers either in circulation or within dysfunctional metabolic tissues are well established. The presence of these factors can, to some extent, predict disease development and progression. A central role is played by the presence of dysfunctional adipose tissue, liver dysfunction, and skeletal muscle dysfunction, which collectively contribute to the increased circulatory levels of proinflammatory factors. Weight loss and classical metabolic interventions achieve a decrease in many of these factors' circulating levels, implying that a better understanding of the processes or even the modulation of inflammation may alleviate these diseases. This review suggests that inflammation plays a significant role in the development and progression of these conditions and that measuring inflammatory markers may be useful for assessing disease risk and development of future treatment methods.
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Affiliation(s)
- Ioannis G Lempesis
- Department of Infectious Diseases-COVID-19 Unit, Laiko General Hospital, Athens 11527, Greece
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Yadav AK, Sata TN, Verma D, Sah AK, Mishra AK, Mrinalini, Hossain MM, Pant K, Venugopal SK. Free fatty acid-induced miR-22 inhibits gluconeogenesis via SIRT-1-mediated PGC-1α expression in nonalcoholic fatty liver disease. ILIVER 2023; 2:1-9. [DOI: 10.1016/j.iliver.2023.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ramanathan R, Ali AH, Ibdah JA. Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23137280. [PMID: 35806284 PMCID: PMC9267060 DOI: 10.3390/ijms23137280] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.
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Affiliation(s)
- Raghu Ramanathan
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
| | - Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: +573-882-7349; Fax: +573-884-4595
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Effect of Siberian Ginseng Water Extract as a Dietary Additive on Growth Performance, Blood Biochemical Indexes, Lipid Metabolism, and Expression of PPARs Pathway-Related Genes in Genetically Improved Farmed Tilapia (Oreochromis niloticus). FISHES 2022. [DOI: 10.3390/fishes7040149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Overnutrition in high-density aquaculture can negatively affect the health of farmed fish. The Chinese herbal medicine Siberian ginseng (Acanthopanax senticosus, AS) can promote animal growth and immunity, and regulate lipid metabolism. Therefore, we conducted an 8-week experiment, in which Oreochromis niloticus was fed with a diet supplemented with different concentrations of AS water extract (ASW) (0‰, 0.1‰, 0.2‰, 0.4‰, 0.8‰, and 1.6‰). The ASW improved the growth performance and increased the specific growth rate (SGR). Linear regression analysis based on the SGR estimated that the optimal ASW amount was 0.74‰. Dietary supplementation with 0.4–0.8‰ ASW reduced the triglyceride and total cholesterol levels in the serum and liver, and regulated lipid transport by increasing the high-density lipoprotein cholesterol concentration and lowering the low-density lipoprotein cholesterol concentration. Dietary supplementation with ASW increased the activities of superoxide dismutase and catalase in the liver, thereby improving the antioxidant capacity. Moreover, ASW modulated the transcription of genes in the peroxisome proliferator-activated receptor signaling pathway in the liver (upregulation of PPARα, APOA1b, and FABP10a and downregulation of PPARγ), thereby regulating fatty acid synthesis and metabolism and slowing fat deposition. These results showed that 0.4–0.8‰ ASW can slow fat deposition and protected the liver from cell damage and abnormal lipid metabolism.
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Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23116270. [PMID: 35682957 PMCID: PMC9181097 DOI: 10.3390/ijms23116270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/28/2022] [Accepted: 05/29/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.
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Affiliation(s)
- Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
- Correspondence: ; Tel.: +81-72-804-0101; Fax: +81-72-804-2524
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Koichi Tsuneyama
- Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
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Cianci N, Subhani M, Hill T, Khanna A, Zheng D, Sheth A, Crooks C, Aithal GP. Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: A systematic review and meta-analysis. World J Hepatol 2022; 14:1025-1037. [PMID: 35721296 PMCID: PMC9157703 DOI: 10.4254/wjh.v14.i5.1025] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/28/2022] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) represents a growing public health concern, with patients having higher risk of morbidity and mortality. It has a considerably high prevalence in the general population, estimated 20%-40% in Europe, and is asymptomatic until late in the disease course. It is therefore important to identify and validate tools that predict hard outcomes such as mortality for use in clinical practice in risk-stratifying NAFLD patients. AIM To evaluate available evidence on the use of non-invasive test(s) as prognostic factors for mortality in NAFLD. METHODS We performed electronic searches of Medline and EMBASE (Ovid) until 7th January 2021 of studies in NAFLD populations. Prognostic markers included serum biomarkers, non-invasive scoring systems, and non-invasive imaging. The population included all spectrums of disease severity, including NAFLD and non-alcoholic steatohepatitis (NASH). Outcomes included all-cause, and cardiovascular mortality. All non-invasive tests were synthesised in a narrative systematic review. Finally, we conducted a meta-analysis of non-invasive scoring systems for predicting all-cause and cardiovascular mortality, calculating pooled hazard ratios and 95% confidence (STATA 16.1). RESULTS Database searches identified 2850 studies - 24 were included. 16 studies reported non-invasive scoring systems, 10 studies reported individual biomarkers, and 1 study reported imaging modalities. 4 studies on non-invasive scoring systems (6324 participants) had data available for inclusion in the meta-analysis. The non-invasive scoring system that performed best at predicting all-cause mortality was NAFLD fibrosis score (NFS) [pHR 3.07 (1.62-5.83)], followed by fibrosis-4 index [pHR 3.06 (1.54-6.07)], BARD [pHR 2.87 (1.27-6.46)], and AST to platelet ratio index [pHR 1.90 (1.32-2.73)]. NFS was also prognostic of cardiovascular-related mortality [pHR 3.09 (1.78-5.34)]. CONCLUSION This study reaffirms that non-invasive scoring systems, especially NFS, are reliable prognostic markers of all-cause mortality and cardiovascular mortality in NAFLD patients. These findings can inform clinical practice in risk stratifying NAFLD patients.
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Affiliation(s)
- Nicole Cianci
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford OX3 9DU, United Kingdom
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom.
| | - Mohsan Subhani
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Trevor Hill
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Amardeep Khanna
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
- King’s Liver Transplant Unit, King's College Hospital, London SE5 9RS, United Kingdom
- NIHR Biomedical Research Center, Freeman Hospital and Newcastle University, Newcastle upon Tyne NE7 7DN, United Kingdom
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
| | - Dong Zheng
- School of Medicine, Queen Mary University London, London E1 4NS, United Kingdom
| | - Abhishek Sheth
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Colin Crooks
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases NIHR Biomedical Research Centre and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
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Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: A systematic review and meta-analysis. World J Hepatol 2022. [DOI: 10.4254/wjh.v14.i5.1026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
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Mitochondrial Dysfunction and Acute Fatty Liver of Pregnancy. Int J Mol Sci 2022; 23:ijms23073595. [PMID: 35408956 PMCID: PMC8999031 DOI: 10.3390/ijms23073595] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 01/27/2023] Open
Abstract
The liver is one of the richest organs in mitochondria, serving as a hub for key metabolic pathways such as β-oxidation, the tricarboxylic acid (TCA) cycle, ketogenesis, respiratory activity, and adenosine triphosphate (ATP) synthesis, all of which provide metabolic energy for the entire body. Mitochondrial dysfunction has been linked to subcellular organelle dysfunction in liver diseases, particularly fatty liver disease. Acute fatty liver of pregnancy (AFLP) is a life-threatening liver disorder unique to pregnancy, which can result in serious maternal and fetal complications, including death. Pregnant mothers with this disease require early detection, prompt delivery, and supportive maternal care. AFLP was considered a mysterious illness and though its pathogenesis has not been fully elucidated, molecular research over the past two decades has linked AFLP to mitochondrial dysfunction and defects in fetal fatty-acid oxidation (FAO). Due to deficient placental and fetal FAO, harmful 3-hydroxy fatty acid metabolites accumulate in the maternal circulation, causing oxidative stress and microvesicular fatty infiltration of the liver, resulting in AFLP. In this review, we provide an overview of AFLP and mitochondrial FAO followed by discussion of how altered mitochondrial function plays an important role in the pathogenesis of AFLP.
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Di Sessa A, Guarino S, Passaro AP, Liguori L, Umano GR, Cirillo G, Miraglia Del Giudice E, Marzuillo P. NAFLD and renal function in children: is there a genetic link? Expert Rev Gastroenterol Hepatol 2021; 15:975-984. [PMID: 33851883 DOI: 10.1080/17474124.2021.1906649] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Over the past decades, a large amount of both adult and pediatric data has shown relationship between Nonalcoholic Fatty Liver Disease (NAFLD) and chronic kidney disease (CKD), resulting in an overall increased cardiometabolic burden. In view of the remarkable role of the genetic background in the NAFLD pathophysiology, a potential influence of the major NAFLD polymorphisms (e.g. the I148M variant of the Patatin-like phospholipase containing domain 3 (PNPLA3) gene, the E167K allele of the Transmembrane 6 superfamily member 2 (TM6SF2), the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), and the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) genes) on renal function has been supposed. A shared metabolic and proinflammatory pathogenesis has been hypothesized, but the exact mechanism is still unknown.Areas covered: We provide a comprehensive review of the potential genetic link between NAFLD and CKD in children. Convincing both adult and pediatric evidence supports this association, but there is some dispute especially in childhood.Expert opinion: Evidence supporting a potential genetic link between NAFLD and CKD represents an intriguing aspect with a major clinical implication because of its putative role in improving strategy programs to counteract the higher cardiometabolic risk of these patients.
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Affiliation(s)
- Anna Di Sessa
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Stefano Guarino
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Antonio Paride Passaro
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Laura Liguori
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Giuseppina Rosaria Umano
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Grazia Cirillo
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Pierluigi Marzuillo
- Department of Woman Child and of General and Specialized Surgery, Università Degli Studi Della Campania "Luigi Vanvitelli", Napoli, Italy
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14
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Morio B, Panthu B, Bassot A, Rieusset J. Role of mitochondria in liver metabolic health and diseases. Cell Calcium 2020; 94:102336. [PMID: 33387847 DOI: 10.1016/j.ceca.2020.102336] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023]
Abstract
The liver is a major organ that coordinates the metabolic flexibility of the whole body, which is characterized by the ability to adapt dynamically in response to fluctuations in energy needs and supplies. In this context, hepatocyte mitochondria are key partners in fine-tuning metabolic flexibility. Here we review the metabolic and signalling pathways carried by mitochondria in the liver, the major pathways that regulate mitochondrial function and how they function in health and metabolic disorders associated to obesity, i.e. insulin resistance, non-alcoholic steatosis and steatohepatitis and hepatocellular carcinoma. Finally, strategies targeting mitochondria to counteract liver disorders are discussed.
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Affiliation(s)
- Béatrice Morio
- CarMeN Laboratory, INSERM U1060, INRA U1397, Lyon, France
| | | | - Arthur Bassot
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G2H7, Canada
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15
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Luo Y, Lin H. Inflammation initiates a vicious cycle between obesity and nonalcoholic fatty liver disease. IMMUNITY INFLAMMATION AND DISEASE 2020; 9:59-73. [PMID: 33332766 PMCID: PMC7860600 DOI: 10.1002/iid3.391] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022]
Abstract
Low‐level of chronic inflammation activation is characteristic of obesity. Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity and is an emerging health problem, it originates from abnormal accumulation of triglycerides in the liver, and sometimes causes inflammatory reactions that could contribute to cirrhosis and liver cancer, thus its pathogenesis needs to be clarified for more treatment options. Once NAFLD is established, it contributes to systemic inflammation, the low‐grade inflammation is continuously maintained during NAFLD causing impaired resolution of inflammation in obesity, which subsequently exacerbates its severity. This study focuses on the effects of obesity‐induced inflammations, which are the underlying causes of the disease progression and development of more severe inflammatory and fibrotic stages. Understanding the relationship between obesity and NAFLD could help in establishing attractive therapeutic targets or diagnostic markers in obesity‐induced inflammation response and provides new approaches for the prevention and treatment of NAFLD in obesity.
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Affiliation(s)
- Yunfei Luo
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
| | - Hui Lin
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
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16
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Kaelin BR, McKenzie CM, Hempel KW, Lang AL, Arteel GE, Beier JI. Adipose tissue-liver crosstalk during pathologic changes caused by vinyl chloride metabolites in mice. Toxicol Appl Pharmacol 2020; 399:115068. [PMID: 32445754 DOI: 10.1016/j.taap.2020.115068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/06/2020] [Accepted: 05/19/2020] [Indexed: 12/20/2022]
Abstract
Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that 'nontoxic' exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.
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Affiliation(s)
- Brenna R Kaelin
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Collin M McKenzie
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Karl W Hempel
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Anna L Lang
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Gavin E Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
| | - Juliane I Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
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17
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Lequoy M, Gigante E, Couty JP, Desbois-Mouthon C. Hepatocellular carcinoma in the context of non-alcoholic steatohepatitis (NASH): recent advances in the pathogenic mechanisms. Horm Mol Biol Clin Investig 2020; 41:/j/hmbci.ahead-of-print/hmbci-2019-0044/hmbci-2019-0044.xml. [PMID: 32112699 DOI: 10.1515/hmbci-2019-0044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 01/16/2020] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC is particularly aggressive and is one of the leading causes of cancer mortality. In recent decades, the epidemiological landscape of HCC has undergone significant changes. While chronic viral hepatitis and excessive alcohol consumption have long been identified as the main risk factors for HCC, non-alcoholic steatohepatitis (NASH), paralleling the worldwide epidemic of obesity and type 2 diabetes, has become a growing cause of HCC in the US and Europe. Here, we review the recent advances in epidemiological, genetic, epigenetic and pathogenic mechanisms as well as experimental mouse models that have improved the understanding of NASH progression toward HCC. We also discuss the clinical management of patients with NASH-related HCC and possible therapeutic approaches.
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Affiliation(s)
- Marie Lequoy
- Service d'Hépato-Gastro-Entérologie, AP-HP, F-75012 Paris, France
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, F-75012 Paris, France
| | - Elia Gigante
- Service d'Hépato-Gastro-Entérologie, AP-HP, F-75012 Paris, France
| | - Jean-Pierre Couty
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France
| | - Christèle Desbois-Mouthon
- Centre de Recherche des Cordeliers, INSERM UMR_S1138, 15 rue de l'école de médecine, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France
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18
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Effects of dietary supplementation with apple peel powder on the growth, blood and liver parameters, and transcriptome of genetically improved farmed tilapia (GIFT, Oreochromis niloticus). PLoS One 2019; 14:e0224995. [PMID: 31714944 PMCID: PMC6850550 DOI: 10.1371/journal.pone.0224995] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/25/2019] [Indexed: 01/30/2023] Open
Abstract
High-density aquaculture and nutritional imbalances may promote fatty liver in genetically improved farmed tilapia (GIFT, Oreochromis niloticus), thus reducing the gains achieved by breeding. In this study, apple peel powder (APP) was used as a feed additive for GIFT. A control group (fed on a diet without APP) and five groups fed on diets supplemented with APP (at 0.05%, 0.1%, 0.2%, 0.4%, or 0.8% of the diet, by weight) were established to investigate the effects of APP on GIFT growth performance and physiological parameters, and on gene expression as determined by transcriptomic analysis. Dietary supplementation with APP at 0.2% promoted GIFT growth, reduced total cholesterol and triacylglycerol levels in the serum and liver, and decreased alanine aminotransferase and aspartate aminotransferase activities in the serum. Gene expression profiles in the liver were compared among the control, 0.2% APP, and 0.8% APP groups, and differentially expressed genes among these groups were identified. Annotation analyses using tools at the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases showed that the differentially expressed genes were mainly involved in the regulation of immunity and fat metabolism. The results showed that excessive supplementation with APP in the diet significantly inhibited the expression of insulin-like growth factor 2 and liver-type fatty acid-binding protein, and stimulated the expression of fatty acid desaturase 2, heat shock protein 90 beta family member 1, and nuclear factor kappa B. This resulted in disordered lipid metabolism and increased pro-inflammatory reactions, which in turn caused liver damage. Therefore, APP has good potential as an environmentally friendly feed additive for GIFT at levels of 0.1%–0.2% in the diet, but excessive amounts can have adverse effects.
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19
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Sangsefidi ZS, Hosseinzadeh M, Ranjbar AM, Akhondi-Meybodi M, Fallahzadeh H, Mozaffari-Khosravi H. The effect of total anthocyanin-base standardized (Cornus mas L.) fruit extract on liver function, tumor necrosis factor α, malondealdehyde, and adiponectin in patients with non-alcoholic fatty liver: a study protocol for a double-blind randomized clinical trial. Nutr J 2019; 18:39. [PMID: 31324181 PMCID: PMC6642510 DOI: 10.1186/s12937-019-0465-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 07/08/2019] [Indexed: 12/25/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Evidence showed that anthocyanins might have effects on NAFLD. Protective effects of Cornelian cherry (Cornus mas L.) extract, as an anthocyanins-rich source, on liver were reported in animal studies. However, very few clinical trials were conducted in this regard. Thus, the aim of this research will be to evaluate the effect of supplementation with total anthocyanin-base standardized cornelian cherry fruit extract on liver function (Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), cytokeratin-18 fragment M30 (CK-18 M30), as well as steatosis and fibrosis of liver), tumor necrosis factor α (TNF-α), malondealdehyde (MDA), and adiponectin in patients with NAFLD. Methods In a double-blind randomized clinical trial, 80 NAFLD patients will be studied. The patients will be randomly assigned into two groups. The intervention group will receive the cornelian cherry extract, containing 320 mg.d− 1 anthocyanins, per day for 12 weeks. The control group will also take the placebo daily for 12 weeks. Liver function (Serum levels of AST, ALT and CK-18 M30; steatosis and fibrosis of liver), serum levels of TNF-α, MDA, and adiponectin will be measured at the baseline and the end of trial for both groups and their results will be compared. Discussion Considering evidences about the useful impacts of anthocyanins on NAFLD, the effects of supplementation with cornelian cherry extract will be investigated on the important variables related to NAFLD. Trial registration Iranian Registry of Clinical Trials (IRCT20180419039359N1).
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Affiliation(s)
- Zohreh Sadat Sangsefidi
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahdieh Hosseinzadeh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Mohammad Ranjbar
- Department of Pharmacognosy, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Herbal Medicine Center, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohsen Akhondi-Meybodi
- Gastroentrology Department, Shahid Sadoughi Hospital, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Fallahzadeh
- Research Center of Prevention and Epidemiology of Non-Communicable Disease, Departments of biostatistics and Epidemiology, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Mozaffari-Khosravi
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. .,Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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20
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Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16:411-428. [PMID: 31028350 DOI: 10.1038/s41575-019-0145-7] [Citation(s) in RCA: 933] [Impact Index Per Article: 155.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.
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Affiliation(s)
- Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
| | - Helen L Reeves
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Northern Institute for Cancer Research, Medical School, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Elena Kotsiliti
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olivier Govaere
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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21
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Li Z, Li Y, Zhang HX, Guo JR, Lam CWK, Wang CY, Zhang W. Mitochondria-Mediated Pathogenesis and Therapeutics for Non-Alcoholic Fatty Liver Disease. Mol Nutr Food Res 2019; 63:e1900043. [PMID: 31199058 DOI: 10.1002/mnfr.201900043] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/03/2019] [Indexed: 12/28/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a worldwide epidemic over the last decade. Remarkable progress has been made in understanding the pathogenesis of NAFLD and, subsequently, in developing medications to treat this disease. Although the mechanisms of NAFLD are complex and multifactorial, accumulating and emerging evidence indicates that mitochondria play a critical role in the pathogenesis and progression of NAFLD. Pharmacologic therapies acting on mitochondria may therefore pave the way to novel strategies for the prevention and protection against NAFLD. This review focuses on new insights into the role of hepatic mitochondrial dysfunction in NAFLD, and summarizes recent studies on mitochondria-centric therapies for NAFLD utilizing new medications or repurposing of currently available drugs. Although some studies presented may feature controversial results or are still in lack of clinical verification, it is undoubted that medications that may spare the mitochondria from multiple levels of damage are highly promising, and have begun to be used with some degree of success.
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Affiliation(s)
- Zheng Li
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Yan Li
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Hui-Xia Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Jian-Ru Guo
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Christopher Wai Kei Lam
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Cai-Yun Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Wei Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
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22
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Salidroside Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease via AMPK-Dependent TXNIP/NLRP3 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8597897. [PMID: 30140371 PMCID: PMC6081551 DOI: 10.1155/2018/8597897] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 04/24/2018] [Accepted: 05/17/2018] [Indexed: 12/23/2022]
Abstract
Our previous studies suggested that salidroside could alleviate hepatic steatosis in type 2 diabetic C57BLKS/Leprdb (db/db) mice. The aim of the present study was to evaluate the therapeutic effect of salidroside on high-fat diet- (HFD-) induced nonalcoholic fatty liver disease (NAFLD) by investigating underlying mechanisms. Mice were fed with HFD or regular diet, randomly divided into two groups, and treated with salidroside or vehicle for 8 weeks. Then, biochemical analyses and histopathological examinations were conducted in vivo and in vitro. Salidroside administration attenuated HFD-induced obesity, blood glucose variability, and hepatic lipid deposition, markedly increasing insulin sensitivity in HFD mice. In addition, salidroside suppressed oxidative stress, thioredoxin-interacting protein (TXNIP) expression, and NLRP3 inflammasome activation in the liver. In cultured hepatocytes, salidroside dose dependently regulated lipid accumulation, reactive oxygen species (ROS) generation, and NLRP3 inflammasome activation as well as improved AMP-activated protein kinase (AMPK) activity and insulin sensitivity. The inhibition of AMPK activation by inhibitor or short interfering RNA (siRNA) resulted in the suppression of the beneficial effects of salidroside in hepatocytes. Our findings demonstrated that salidroside protects against NAFLD by improving hepatic lipid metabolism and NLRP3 inflammasome activation, and these actions are related to the regulation of the oxidative stress and AMPK-dependent TXNIP/NLRP3 pathways.
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23
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Zhang Y, Kim DK, Jung YS, Kim YH, Lee YS, Kim J, Jeong WI, Lee IK, Cho SJ, Dooley S, Lee CH, Choi HS. Inverse agonist of ERRγ reduces cannabinoid receptor type 1-mediated induction of fibrinogen synthesis in mice with a high-fat diet-intoxicated liver. Arch Toxicol 2018; 92:2885-2896. [PMID: 30019168 DOI: 10.1007/s00204-018-2270-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/12/2018] [Indexed: 12/12/2022]
Abstract
Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRγ as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRγ inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated the effect of ACEA (10 µM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites for ERRγ on the mouse FGG promoter. ACEA or adenovirus ERRγ injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRγ knockdown with Ad-shERRγ attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRγ with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia.
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Affiliation(s)
- Yaochen Zhang
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Don-Kyu Kim
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Yoon Seok Jung
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Yong-Hoon Kim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Yong Soo Lee
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Jina Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Won-Il Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.,Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Sung Jin Cho
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.,New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chul-Ho Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Hueng-Sik Choi
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
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24
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Teodoro JS, Varela AT, Duarte FV, Gomes AP, Palmeira CM, Rolo AP. Indirubin and NAD + prevent mitochondrial ischaemia/reperfusion damage in fatty livers. Eur J Clin Invest 2018; 48:e12932. [PMID: 29603199 DOI: 10.1111/eci.12932] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 03/22/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fatty livers are considerably more susceptible to acute stressors, such as ischaemia/reperfusion (I/R). As the incidence of I/R is high due to surgical events and some pathologies, there is an urgent need to find strategies against I/R injury (I/RI) in fatty livers. We postulate that an acute pretreatment with indirubin-3'-oxime (Ind) or NAD+ prevents mitochondrial dysfunction associated with warm I/RI in fatty livers. MATERIALS AND METHODS Zucker fatty rats were subjected to warm ischaemia and 12 hours of reperfusion. Ind or NAD+ was administered in the hepatic artery 30 minutes before ischaemia. Hepatic mitochondrial isolation was performed, and functional assays as well as molecular analysis were performed. RESULTS Pretreatment decreased markers of liver injury while preserving mitochondrial cytochrome c content, which is related to the prevention of calcium-induced mitochondrial permeability transition (mPT), the decline in mitochondrial respiratory state 3 and ATP content. The generation of reactive oxygen species (ROS) was also diminished. Inhibition of GSK-3ß by Ind resulted in the prevention of cyclophilin-D (CypD) phosphorylation, unabling it to bind to the adenine nucleotide translocator (ANT), thus, preventing mPT induction. Furthermore, deacetylation of CypD at Lys residue by sirtuin 3 (SIRT3) caused its dissociation from ANT, contributing to an increase in mPT threshold in NAD+ -pretreated animals. CONCLUSIONS Pretreatment with Ind or NAD+ protects fatty livers by maintaining mitochondrial calcium homoeostasis, thus, preserving mitochondrial function and energetic balance. As such, CypD might be a new protective target against I/RI in fatty livers.
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Affiliation(s)
- João Soeiro Teodoro
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Ana Teresa Varela
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Filipe Valente Duarte
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Ana Patrícia Gomes
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Carlos Marques Palmeira
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Anabela Pinto Rolo
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
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25
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Scorletti E, Byrne CD. Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action. Mol Aspects Med 2018; 64:135-146. [PMID: 29544992 DOI: 10.1016/j.mam.2018.03.001] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 03/07/2018] [Accepted: 03/09/2018] [Indexed: 02/07/2023]
Abstract
For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised trials in both adults and children with NAFLD; and finally to discuss key 'known unknowns' that need to be considered, before planning future studies that are focussed on testing the effects of omega-3 fatty acid treatment in patients with NAFLD.
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Affiliation(s)
- Eleonora Scorletti
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; National Institute for Health Research, Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
| | - Christopher D Byrne
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; National Institute for Health Research, Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
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26
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Li M, Sirko S. Traumatic Brain Injury: At the Crossroads of Neuropathology and Common Metabolic Endocrinopathies. J Clin Med 2018. [PMID: 29538298 PMCID: PMC5867585 DOI: 10.3390/jcm7030059] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Building on the seminal work by Geoffrey Harris in the 1970s, the neuroendocrinology field, having undergone spectacular growth, has endeavored to understand the mechanisms of hormonal connectivity between the brain and the rest of the body. Given the fundamental role of the brain in the orchestration of endocrine processes through interactions among neurohormones, it is thus not surprising that the structural and/or functional alterations following traumatic brain injury (TBI) can lead to endocrine changes affecting the whole organism. Taking into account that systemic hormones also act on the brain, modifying its structure and biochemistry, and can acutely and chronically affect several neurophysiological endpoints, the question is to what extent preexisting endocrine dysfunction may set the stage for an adverse outcome after TBI. In this review, we provide an overview of some aspects of three common metabolic endocrinopathies, e.g., diabetes mellitus, obesity, and thyroid dysfunction, and how these could be triggered by TBI. In addition, we discuss how the complex endocrine networks are woven into the responses to sudden changes after TBI, as well as some of the potential mechanisms that, separately or synergistically, can influence outcomes after TBI.
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Affiliation(s)
- Melanie Li
- Physiological Genomics, Biomedical Center (BMC), Institute of Physiology, Medical Faculty of the Ludwig-Maximilian University Munich, 82152 Planegg-Martinsried, Germany.
| | - Swetlana Sirko
- Physiological Genomics, Biomedical Center (BMC), Institute of Physiology, Medical Faculty of the Ludwig-Maximilian University Munich, 82152 Planegg-Martinsried, Germany.
- Institute of Stem Cell Research, Helmholtz Center Munich, Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.
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27
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Jung Y, Park J, Kim HL, Sim JE, Youn DH, Kang J, Lim S, Jeong MY, Yang WM, Lee SG, Ahn KS, Um JY. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro. FASEB J 2018; 32:1388-1402. [PMID: 29141998 DOI: 10.1096/fj.201700231rr] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Energy expenditure is a target gaining recent interest for obesity treatment. The antiobesity effect of vanillic acid (VA), a well-known flavoring agent, was investigated in vivo and in vitro. High-fat diet (HFD)-induced obese mice and genetically obese db/db mice showed significantly decreased body weights after VA administration. Two major adipogenic markers, peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), were reduced while the key factor of energy metabolism, AMPKα, was increased in the white adipose tissue and liver tissue of VA-treated mice. Furthermore, VA inhibited lipid accumulation and reduced hepatotoxic/inflammatory markers in liver tissues of mice and HepG2 hepatocytes. VA treatment also decreased differentiation of 3T3-L1 adipocytes by regulating adipogenic factors including PPARγ and C/EBPα. AMPKα small interfering RNA was used to examine whether AMPK was associated with the actions of VA. In AMPKα-nulled 3T3-L1 cells, the inhibitory action of VA on PPARγ and C/EBPα was attenuated. Furthermore, in brown adipose tissues of mice and primary cultured brown adipocytes, VA increased mitochondria- and thermogenesis-related factors such as uncoupling protein 1 and PPARγ-coactivator 1-α. Taken together, our results suggest that VA has potential as an AMPKα- and thermogenesis-activating antiobesity agent.-Jung, Y., Park, J., Kim, H.-L., Sim, J.-E., Youn, D.-H., Kang, J., Lim, S., Jeong, M.-Y., Yang, W. M., Lee, S.-G., Ahn, K. S., Um, J.-Y. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro.
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Affiliation(s)
- Yunu Jung
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Jinbong Park
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Hye-Lin Kim
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Jung-Eun Sim
- Department of Biological Sciences in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Dong-Hyun Youn
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea
| | - JongWook Kang
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Seona Lim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Mi-Young Jeong
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Woong Mo Yang
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Seok-Geun Lee
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Kwang Seok Ahn
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
| | - Jae-Young Um
- College of Korean Medicine and Basic Research Laboratory for Comorbidity Regulation, Kyung Hee University, Seoul, South Korea
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28
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Lee YH, Kim SH, Kim SN, Kwon HJ, Kim JD, Oh JY, Jung YS. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease. Oncotarget 2018; 7:46959-46971. [PMID: 27409675 PMCID: PMC5216916 DOI: 10.18632/oncotarget.10506] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/30/2016] [Indexed: 02/06/2023] Open
Abstract
Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.
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Affiliation(s)
- Yun-Hee Lee
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Sou Hyun Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Sang-Nam Kim
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Hyun-Jung Kwon
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Jeong-Dong Kim
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Ji Youn Oh
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Young-Suk Jung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
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29
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Lepreux S, Villeneuve J, Dewitte A, Bérard AM, Desmoulière A, Ripoche J. CD40 signaling and hepatic steatosis: Unanticipated links. Clin Res Hepatol Gastroenterol 2017; 41:357-369. [PMID: 27989689 DOI: 10.1016/j.clinre.2016.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 10/10/2016] [Accepted: 11/07/2016] [Indexed: 02/08/2023]
Abstract
Obesity predisposes to an increased risk of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is the key pathological feature of NAFLD and has emerged as a metabolic disorder in which innate and adaptive arms of the immune response play a central role in disease pathogenesis. Recent studies have revealed unexpected relationships between CD40 signaling and hepatic steatosis in high fat diet rodent models. CD154, the ligand of CD40, is a mediator of inflammation and controls several critical events of innate and adaptive immune responses. In the light of these reports, we discuss potential links between CD40 signaling and hepatic steatosis in NAFLD.
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Affiliation(s)
| | - Julien Villeneuve
- Cell and Developmental Biology Programme, Centre for Genomic Regulation, 08003 Barcelona, Spain
| | - Antoine Dewitte
- Service d'Anesthésie-Réanimation II, CHU de Bordeaux, 33600 Pessac, France
| | - Annie M Bérard
- Service de Biochimie, CHU de Bordeaux, 33000 Bordeaux, France
| | | | - Jean Ripoche
- INSERM U1026, Université de Bordeaux, 33000 Bordeaux, France.
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30
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Atilano-Roque A, Roda G, Fogueri U, Kiser JJ, Joy MS. Effect of Disease Pathologies on Transporter Expression and Function. J Clin Pharmacol 2017; 56 Suppl 7:S205-21. [PMID: 27385176 DOI: 10.1002/jcph.768] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/08/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022]
Abstract
Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.
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Affiliation(s)
- Amandla Atilano-Roque
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Gavriel Roda
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Uma Fogueri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Jennifer J Kiser
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Melanie S Joy
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.,Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA
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31
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Zhang Y, Kim DK, Lu Y, Jung YS, Lee JM, Kim YH, Lee YS, Kim J, Dewidar B, Jeong WIL, Lee IK, Cho SJ, Dooley S, Lee CH, Li X, Choi HS. Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression. PLoS One 2017; 12:e0182141. [PMID: 28750085 PMCID: PMC5531639 DOI: 10.1371/journal.pone.0182141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022] Open
Abstract
Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.
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Affiliation(s)
- Yaochen Zhang
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Don-Kyu Kim
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Yan Lu
- Shanghai Institute of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yoon Seok Jung
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Ji-min Lee
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Young-Hoon Kim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Yong Soo Lee
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Jina Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Bedair Dewidar
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Won-IL Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
- Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Korea
| | - Sung Jin Cho
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
- Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Korea
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chul-Ho Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Xiaoying Li
- Shanghai Institute of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hueng-Sik Choi
- National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
- * E-mail:
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王 鹤, 孙 鹏, 刘 克. 肝脏转运体表达和功能的变化对肝疾病的影响. Shijie Huaren Xiaohua Zazhi 2017; 25:1427-1437. [DOI: 10.11569/wcjd.v25.i16.1427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
转运体是药物吸收、分布、代谢和排泄的重要决定因素, 在肝脏表达尤为广泛. 肝脏转运体可以摄取大多数内源性物质、营养物质和外源性物质进入肝脏, 在肝脏内经过一系列的代谢转化, 最终将其外排入胆汁, 并由胆汁排到肝外. 越来越多的证据表明, 肝脏疾病状态下转运体的表达和功能会发生改变, 影响药物在体内的处置过程, 进而增加药物相互作用的可能性, 同时加大了疾病药物治疗的难度. 本文从肝脏摄取型和外排型转运体两方面出发, 针对肝脏转运体表达和功能的变化对肝疾病的影响作一综述.
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Miguel FM, Schemitt EG, Colares JR, Hartmann RM, Morgan-Martins MI, Marroni NP. ACTION OF VITAMIN E ON EXPERIMENTAL SEVERE ACUTE LIVER FAILURE. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:123-129. [PMID: 28198914 DOI: 10.1590/s0004-2803.201700000-03] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 11/28/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Severe Acute Liver Failure (ALF) is a life-threatening clinical syndrome characterized by hepatocyte necrosis, loss of hepatic architecture, and impairment of liver functions. One of the main causes of ALF is hepatotoxicity from chemical agents, which damage hepatocytes and result in increase of reactive oxygen species. The vitamin E isoform is the one with the strongest biological antioxidant activity. OBJECTIVE To evaluate the antioxidant effect of vitamin E in this ALF model. METHODS We used 56 rats (mean weight of 300 g) divided into eight groups, four groups assessed at 24 hours and 4 assessed at 48 hours after induction: control group (CO); Vitamin E (Vit. E); Thioacetamide (TAA) and Thioacetamide + Vitamina E (TAA+Vit.E). Rats were submitted to injections of thioacetamide (400 mg/kg i.p.) at baseline and 8 hours later. Vitamin E (100 mg/kg ip) was administered 30 minutes after the second dose of thioacetamide. The 48-hour group rats received two additional doses of vitamin E (24h and 36h). At 24h or 48 hours after the administration of the first dose of TAA, rats were weighed and anesthetized and their blood sampled for evaluation of liver integrity through enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Liver tissue was sampled for assessment of lipid peroxidation (LPO) by the technique TBARS, antioxidant enzymes SOD, CAT, GPx and GST activity, levels of the NO 2 /NO 3 and histology by H&E in two times. The results were expressed as mean ± standard deviation and statistically analyzed by ANOVA followed by Student-Newman-Keuls, with P <0.05 considered as significant. RESULTS After treatment with vitamin E, we observed a reduction in liver enzymes AST (U/L) (101.32±19.45 in 24 hours and 97.85±29.65 in 48 hours) related to the TAA group (469.56± 0.69 in 24 hours and 598.23±55.45 in 48 hours) and ALT (U/L) (76.59±8.56 in 24 hours and 68.47±6.49 in 48 hours) compared to the TAA group (312.21±10.23 in 24 hours and 359.15±17.58 in 48 hours). There was a reduction of LPO (nmol/mg Prot) in the TAA+Vit.E group (0.77±0.07 in 24 hours and 0.95±0.08 in 48 hours) compared to the TAA group (1.50±0.07 in 24 hours e 1.65±0.16 in 48 hours). SOD decreased in the TAA+Vit.E group (49.48±9.47 in 24 hours and 62.45±18, 47 in 48 hours), related to the TAA group (98.46±15.48 in 24 hours and 154.13±21.46 in 48 hours), as well as GST (nmol/min/mg Prot) in the TAA+Vit.E group (350.57±36.93 in 24 hours and 453.29±13.84 in 48 hours) compared to the TAA group (561.57±64.56 in 24 hours and 673.43±38.13 in 48 hours). There was an increase in CAT (pmol/min/mg Prot) in the TAA+Vit.E group (3.40±0.44 in 24 hours and 3.0±0.35 in 48 hours) compared to the TAA group (1.65±0.21 in 24 hours and 1.86±0.42 in 48 hours). The GPx (nmol/min/mg Prot) increased in 24 hours in the TAA+Vit.E group (1.01±0.16) compared to the TAA group (0.41±0.04) and decreased in 48 hours (1.19±0.17) compared to the TAA group (1.76±0.21). There was a reduction in NO2/NO3 (mmol/L) levels in the TAA+Vit.E group (31.47±4.26 in 24 hours and 38.93±5.20 in 48 hours) compared to the TAA group (49.37±5.12 in 24 hours and 53.53±5.97 in 48 hours). The histopathological evaluation showed a decrease in liver injury (necrosis and inflammation) in both studied times. CONCLUSION These results suggest that vitamin E was able to protect the liver from lesions caused by thioacetamide.
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Affiliation(s)
- Fabiano Moraes Miguel
- Programa de Pós-Graduação BioSaúde, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Laboratório de Estresse Oxidativo e Antioxidantes, Universidade Luterana do Brasil, Canoas, RS, Brazil
| | - Elizângela Gonçalves Schemitt
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Laboratório de Estresse Oxidativo e Antioxidantes, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Laboratório de Hepatologia e Gastroenterologia Experimental, Hospital de Clínicas de Porto Alegre, RS, Brazil
| | - Josieli Raskopf Colares
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Laboratório de Estresse Oxidativo e Antioxidantes, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Laboratório de Hepatologia e Gastroenterologia Experimental, Hospital de Clínicas de Porto Alegre, RS, Brazil
| | - Renata Minuzzo Hartmann
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Laboratório de Estresse Oxidativo e Antioxidantes, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Laboratório de Hepatologia e Gastroenterologia Experimental, Hospital de Clínicas de Porto Alegre, RS, Brazil
| | | | - Norma Possa Marroni
- Programa de Pós-Graduação BioSaúde, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Programa de Pós-Graduação em Ciências Biológicas: Fisiologia Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Laboratório de Estresse Oxidativo e Antioxidantes, Universidade Luterana do Brasil, Canoas, RS, Brazil.,Laboratório de Hepatologia e Gastroenterologia Experimental, Hospital de Clínicas de Porto Alegre, RS, Brazil
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Ahmadian E, Pennefather PS, Eftekhari A, Heidari R, Eghbal MA. Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention. Expert Rev Gastroenterol Hepatol 2016; 10:1279-1288. [PMID: 27352778 DOI: 10.1080/17474124.2016.1207523] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease. Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS. Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.
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Affiliation(s)
- Elham Ahmadian
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,b Biotechnology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,c Pharmacology and Toxicology Department, School of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.,d Students Research Committee , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Peter S Pennefather
- e Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada
| | - Aziz Eftekhari
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,d Students Research Committee , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Reza Heidari
- f Pharmaceutical Sciences Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.,g Gerash School of Paramedical Sciences , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammad Ali Eghbal
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,b Biotechnology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,c Pharmacology and Toxicology Department, School of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran
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Koronowicz AA, Banks P, Szymczyk B, Leszczyńska T, Master A, Piasna E, Szczepański W, Domagała D, Kopeć A, Piątkowska E, Laidler P. Dietary conjugated linoleic acid affects blood parameters, liver morphology and expression of selected hepatic genes in laying hens. Br Poult Sci 2016; 57:663-673. [PMID: 27267260 DOI: 10.1080/00071668.2016.1192280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The objective of this research were to investigate the effect of a conjugated linoleic acid (CLA)-enriched diet on Isa Brown laying hen health status and to provide a comprehensive analysis of changes in blood parameters, liver morphology and selected hepatic gene expression. Hens were allocated to the control and experimental group (diet enriched with 0.75% CLA) for a total period of 4 m. At the end of the experiment half of the hens from each group were slaughtered for analyses. The remaining hens were transferred to an organic farm for the next 5 m and fed on the diet without CLA supplementation. The CLA-enriched diet resulted in significant changes in blood and serum parameters; specifically, haematocrit (HCT), mean corpuscular volume (MCV) and white blood cells (WBC) count were decreased compared to the control. The total cholesterol (TC) was not significantly affected while the triacylglycerol's (TG) concentration was elevated. The activity of alanine aminotransferase (ALT) was significantly increased in the CLA-supplemented group, while aspartate aminotransferase (AST) showed an increasing tendency. Liver biopsies showed pathological changes classified as non-alcoholic fatty liver disease (NAFLD). Additionally, the expression of hepatic genes involved in fatty acids synthesis (ME1, ACLY, ACC, FASN, SCD1), oxidation (CPT1α, PPARA), detoxification processes (Cytochrome P450, CYP, Flavin-containing monooxygenase, FMO3), oxidative stress (NOX4, XbP1) and inflammation (IL6, TNFα) were elevated. Cessation of CLA supplementation for 5 m of organic farming resulted in normalisation of blood and hepatic parameters to the levels observed in control hens. The results of this study indicate that dietary CLA triggers an integrated stress response in laying hens and activates mechanisms involved in liver detoxification.
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Affiliation(s)
- A A Koronowicz
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - P Banks
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - B Szymczyk
- b Department of Animal Nutrition and Feed Science , National Research Institute of Animal Production , Krakow , Poland
| | - T Leszczyńska
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - A Master
- c Department of Biochemistry and Molecular Biology , Medical Centre for Postgraduate Education , Warszawa , Poland
| | - E Piasna
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - W Szczepański
- d Department of Pathomorphology , Jagiellonian University Medical College , Krakow , Poland
| | - D Domagała
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - A Kopeć
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - E Piątkowska
- a Department of Human Nutrition, Faculty of Food Technology , University of Agriculture , Krakow , Poland
| | - P Laidler
- e Department of Medical Biochemistry , Jagiellonian University Medical College , Krakow , Poland
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Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61:1294-303. [PMID: 26841783 PMCID: PMC4948286 DOI: 10.1007/s10620-016-4049-x] [Citation(s) in RCA: 368] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023]
Abstract
Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.
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Affiliation(s)
- Marco Arrese
- Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Daniel Cabrera
- Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile
| | - Alexis M Kalergis
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA, USA.
- Rady Children's Hospital, San Diego, CA, USA.
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSD, 3020 Children's Way, MC 5030, San Diego, CA, 92103-8450, USA.
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Wree A, Mehal WZ, Feldstein AE. Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis. Semin Liver Dis 2016; 36:27-36. [PMID: 26870930 PMCID: PMC4955833 DOI: 10.1055/s-0035-1571272] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease represents a wide spectrum of conditions and is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. Great effort has been focused on the development of novel therapies for those patients with the more advanced forms of the disease, in particular those with nonalcoholic steatohepatitis (NASH) and liver fibrosis that can be associated with significant morbidity and mortality. In this review, the authors focus on the role of cell death and sterile inflammatory pathways as well as the self-perpetuating deleterious cycle they may trigger as novel therapeutic targets for the treatment of fibrotic NASH.
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Affiliation(s)
- Alexander Wree
- Department of Pediatrics, University of California San Diego (UCSD), and Rady Children’s Hospital, San Diego, California,Department of Internal Medicine III, University Hospital, RWTH-Aachen, Germany
| | - Wajahat Z. Mehal
- Yale University, and West Haven Veterans Medical Center, New Haven, Connecticut
| | - Ariel E. Feldstein
- Department of Pediatrics, University of California San Diego (UCSD), and Rady Children’s Hospital, San Diego, California
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Oliveira CP, de Lima Sanches P, de Abreu-Silva EO, Marcadenti A. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease. J Diabetes Res 2016; 2016:4597246. [PMID: 26770987 PMCID: PMC4685119 DOI: 10.1155/2016/4597246] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 07/26/2015] [Accepted: 07/29/2015] [Indexed: 12/26/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD.
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Affiliation(s)
- Claudia P. Oliveira
- Department of Gastroenterology, School of Medicine, University of Sao Paulo (USP), 255 Dr. Enéas de Carvalho Aguiar Avenue, Cerqueira César, 05403-900 Sao Paulo, SP, Brazil
| | - Priscila de Lima Sanches
- Postgraduate Program in Nutrition, Federal University of Sao Paulo (UNIFESP), 630 Marselhesa Street, Vila Clementino, 04020-060 Sao Paulo, SP, Brazil
| | - Erlon Oliveira de Abreu-Silva
- Division of Interventional Cardiology and Postgraduate Program in Cardiology, Federal University of Sao Paulo (UNIFESP), 715 Napoleao de Barros Street, Vila Clementino, 04024-002 Sao Paulo, SP, Brazil
| | - Aline Marcadenti
- Department of Nutrition, Federal University of Health Sciences of Porto Alegre (UFCSPA), 245 Sarmento Leite Street, Centro Histórico, 90050-170 Porto Alegre, RS, Brazil
- Postgraduate Program in Health Sciences: Cardiology, Institute of Cardiology of Rio Grande do Sul (IC/FUC), 395 Princesa Isabel Avenue, Santana, 90040-371 Porto Alegre, RS, Brazil
- *Aline Marcadenti:
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Maruyama H, Kiyono S, Kondo T, Sekimoto T, Yokosuka O. Palmitate-induced Regulation of PPARγ via PGC1α: a Mechanism for Lipid Accumulation in the Liver in Nonalcoholic Fatty Liver Disease. Int J Med Sci 2016; 13:169-78. [PMID: 26941577 PMCID: PMC4773281 DOI: 10.7150/ijms.13581] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023] Open
Abstract
The aim was to examine the effect of free fatty acids on the regulation of PPARγ-PGC1α pathway, and the effect of PPARγ/PGC1α in NAFLD. The mRNA and protein expression of PGC1α and phospho/total PPARγ were examined in Huh7 cells after the palmitate/oleate treatment with/without the transfection with siRNA against PGC1a. The palmitate content, mRNA and protein expression of PGC1α and PPARγ in the liver were examined in the control and NAFLD mice. Palmitate (500 μM), but not oleate, increased protein expression of PGC1α and phospho PPARγ (PGC1α, 1.42-fold, P=0.038; phospho PPARγ, 1.56-fold, P=0.022). The palmitate-induced PPARγ mRNA expression was reduced after the transfection (0.46‑fold), and the protein expressions of PGC1α (0.52-fold, P=0.019) and phospho PPARγ (0.43-fold, P=0.011) were suppressed in siRNA-transfected cells. The palmitate (12325.8 ± 1758.9 μg/g vs. 6245.6 ± 1182.7 μg/g, p=0.002), and mRNA expression of PGC1α (11.0 vs. 5.5, p=0.03) and PPARγ (4.3 vs. 2.2, p=0.0001) in the liver were higher in high-triglyceride liver mice (>15.2 mg/g) than in low-triglyceride liver mice (<15.2 mg/g). The protein expressions of both PGC1α and PPARγ were higher in the NAFLD group than in the controls (PGC1α, 1.41-fold, P=0.035; PPARγ, 1.39-fold, P=0.042), and were higher in the high-triglyceride liver group (PGC1α, 1.52-fold, p=0.03; PPARγ, 1.22-fold, p=0.05) than in the low-triglyceride liver group. In conclusion, palmitate appear to up-regulate PPARγ via PGC1α in Huh7 cells, and both PGC1α and PPARγ are up-regulated in the NAFLD mice liver, suggesting an effect on lipid metabolism leading to intrahepatic triglyceride accumulation.
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Affiliation(s)
- Hitoshi Maruyama
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Tadashi Sekimoto
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
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Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:3529149. [PMID: 26798419 PMCID: PMC4699024 DOI: 10.1155/2016/3529149] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 10/11/2015] [Indexed: 12/16/2022]
Abstract
Hepatic diseases are a major concern worldwide. Increased specific plasma enzyme activities are considered diagnostic features for liver diseases, since enzymes are released into the blood compartment following the deterioration of the organ. Release of liver mitochondrial enzymes is considered strong evidence for hepatic necrosis, which is associated with an increased production of ROS, often leading to greater hepatic lipid peroxidation. Lipotoxic mediators and intracellular signals activated Kupffer cells, which provides evidence strongly suggesting the participation of oxidant stress in acute liver damage, inducing the progression of liver injury to chronic liver damage. Elevated transaminase activities are considered as an index marker of hepatotoxicity, linked to oxidant stress. However, a drastic increase of serum activities of liver enzyme markers ought not necessarily to reflect liver cell death. In fact, increased serum levels of cytoplasmic enzymes have readily been observed after partial hepatectomy (PH) in the regenerating liver of rats. In this regard, we are now showing that in vitro modifications of the oxidant status affect differentially the release of liver enzymes, indicating that this release is a strictly controlled event and not directly related to the onset of oxidant stress of the liver.
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Genetic polymorphisms and oxidative stress in non-alcoholic steatohepatitis (NASH): A mini review. Clin Res Hepatol Gastroenterol 2015; 39 Suppl 1:S35-40. [PMID: 26160475 DOI: 10.1016/j.clinre.2015.05.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 05/18/2015] [Accepted: 05/20/2015] [Indexed: 02/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease, thus becoming an epidemic in the Western world with a major impact on public health. NAFLD encompasses a large spectrum of disease ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and may progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The role of genetic polymorphisms is not clear. Evidence supports the hypothesis that genetic factors are involved in the predisposition to NAFLD, and thus should emphasize the polygenic nature of the disease as a limiting factor in these studies. However, the polymorphic allele associated with increased hepatic steatosis appears to be associated with various different combinations of phenotypes, including increase or decrease of the biochemical and clinical parameters. It is possible that SNPs in genes involved in excessive fatty acid oxidation would predispose to NASH. On the other hand, the SNPs could determine the inadequate mitochondrial overload during times of excessive FFA supply. However due to the multiple hits involving some pathways, a brief review of genetic variants on mediators of oxidative stress, inflammation and lipid metabolism pathways is presented. It is clear that the discovery of genetic and environmental associations, robust enough to direct the treatment and to trace specific prevention strategies would only be possible with studies examining the susceptibility of NAFLD in a number of individuals considerably higher than assessed so far. These studies need a large number of well phenotyped cases and controls and certainly require national and international collaboration.
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Spengler EK, Loomba R. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Mayo Clin Proc 2015; 90. [PMID: 26219858 PMCID: PMC4567478 DOI: 10.1016/j.mayocp.2015.06.013] [Citation(s) in RCA: 197] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease in the United States, afflicting an estimated 80 to 100 million Americans. Nonalcoholic fatty liver disease is a spectrum of liver diseases composed of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Although nonalcoholic fatty liver has a negligible risk of progression, patients with NASH often develop cirrhosis or hepatocellular carcinoma. Although liver biopsy is required to diagnose NASH, only patients with a high risk of NASH or advanced fibrosis require this evaluation. Despite the high prevalence of NAFLD, well-defined screening recommendations are currently lacking. In this review, suggestions for screening, diagnosis, and initial work-up of NAFLD are given on the basis of established guidelines and recent publications. Proposed drug treatments of NASH are also discussed, highlighting the study outcomes, as well as proposed uses and limitations of these drugs. The literature was searched in PubMed using search terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, with filters of "English language." A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.
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Affiliation(s)
- Erin K Spengler
- Division of Gastroenterology, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City
| | - Rohit Loomba
- NAFLD Translational Research Unit, Division of Gastroenterology, Department of Medicine, and Division of Epidemiology, Department of Family and Preventive Medicine, University of California San Diego School of Medicine, La Jolla, CA.
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Yeung ENW, Treskes P, Martin SF, Manning JR, Dunbar DR, Rogers SM, Le Bihan T, Lockman KA, Morley SD, Hayes PC, Nelson LJ, Plevris JN. Fibrinogen production is enhanced in an in-vitro model of non-alcoholic fatty liver disease: an isolated risk factor for cardiovascular events? Lipids Health Dis 2015; 14:86. [PMID: 26256740 PMCID: PMC4529985 DOI: 10.1186/s12944-015-0069-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/29/2015] [Indexed: 12/25/2022] Open
Abstract
Background Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis. Methods Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways. Results The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05). Conclusions In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients. Electronic supplementary material The online version of this article (doi:10.1186/s12944-015-0069-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Emily N W Yeung
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - Philipp Treskes
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - Sarah F Martin
- Kinetic Parameter Facility, SynthSys, Centre for Synthetic and Systems Biology, University of Edinburgh, C.H. Waddington Building, The Kings Buildings, Edinburgh, EH9 3JD, UK.
| | - Jonathan R Manning
- Bioinformatics Team, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
| | - Donald R Dunbar
- Bioinformatics Team, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
| | - Sophie M Rogers
- Kinetic Parameter Facility, SynthSys, Centre for Synthetic and Systems Biology, University of Edinburgh, C.H. Waddington Building, The Kings Buildings, Edinburgh, EH9 3JD, UK.
| | - Thierry Le Bihan
- Kinetic Parameter Facility, SynthSys, Centre for Synthetic and Systems Biology, University of Edinburgh, C.H. Waddington Building, The Kings Buildings, Edinburgh, EH9 3JD, UK.
| | - K Ann Lockman
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - Steven D Morley
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - Peter C Hayes
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - Leonard J Nelson
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
| | - John N Plevris
- Hepatology Laboratory, Division of Health Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
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Kim HY, Park SY, Lee MH, Rho JH, Oh YJ, Jung HU, Yoo SH, Jeong NY, Lee HJ, Suh S, Seo SY, Cheong J, Jeong JS, Yoo YH. Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance. J Hepatol 2015; 63:477-85. [PMID: 25646886 DOI: 10.1016/j.jhep.2015.01.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 01/14/2015] [Accepted: 01/18/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Most studies on the role of STAMP2 in metabolism have used adipose tissue. Little knowledge exists concerning the role of STAMP2 in the liver, which is a metabolically central target. We hypothesized that STAMP2 is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. METHODS We examined our hypothesis using human NAFLD patient pathology samples and a high-fat diet (HFD)-induced NAFLD mouse model. The molecular mechanism underlying hepatic STAMP2-mediated lipid imbalance was explored using an oleic acid (OA)-induced NAFLD in vitro model. RESULTS Noticeably, the expression level of STAMP2 protein was reduced in the livers obtained from NAFLD patients and HFD-induced NAFLD mice. In vivo knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in mice fed a HFD. Conversely, the delivery of adenoviral STAMP2 (Ad-STAMP2) improved hepatic steatosis in HFD-induced NAFLD mice. The expression of lipogenic or adipogenic factors was increased in both in vitro and in vivo NAFLD models but was reversed by Ad-STAMP2. Adenoviral overexpression of STAMP2 improved insulin resistance in the HFD-induced NAFLD mice. In vivo and in vitro assays demonstrated that STAMP2 modulates insulin sensitivity and glucose metabolism and that STAMP2 counteracts OA-induced insulin resistance by modulating insulin receptor substrate-1 stability. CONCLUSIONS The present study revealed that hepatic STAMP2 plays a pivotal role in preventing HFD-induced NAFLD and that STAMP2 overexpression improves hepatic steatosis and insulin resistance in NAFLD. Our findings indicate that STAMP2 may represent a suitable target for interventions targeting NAFLD.
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Affiliation(s)
- Hye Y Kim
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - So Y Park
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Mi H Lee
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Jee H Rho
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Yoo J Oh
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Hye U Jung
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Seung H Yoo
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Na Y Jeong
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Hye J Lee
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - SungHwan Suh
- Department of Endocrinology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - Su Y Seo
- Department of Microbiology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - JaeHun Cheong
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, South Korea
| | - Jin S Jeong
- Department of Pathology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - Young H Yoo
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
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Kong XY, Kase ET, Herskedal A, Schjalm C, Damme M, Nesset CK, Thoresen GH, Rustan AC, Eskild W. Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver. PLoS One 2015; 10:e0129402. [PMID: 26047317 PMCID: PMC4457871 DOI: 10.1371/journal.pone.0129402] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 05/07/2015] [Indexed: 12/25/2022] Open
Abstract
Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1) has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmpgt/gt mice (formerly known as Ncu-g1gt/gtmice) were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmpgt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmpgt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmpgt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmpgt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmpgt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmpgt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmpgt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.
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Affiliation(s)
- Xiang Yi Kong
- Department of Bioscience, University of Oslo, Oslo, Norway
| | - Eili Tranheim Kase
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | | | | | - Markus Damme
- Institute of Biochemistry, Christian-Albrechts-Universität Kiel, Kiel, Germany
| | | | - G. Hege Thoresen
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
- Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Arild C. Rustan
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Winnie Eskild
- Department of Bioscience, University of Oslo, Oslo, Norway
- * E-mail:
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Li M, Guo K, Vanella L, Taketani S, Adachi Y, Ikehara S. Stem cell transplantation upregulates Sirt1 and antioxidant expression, ameliorating fatty liver in type 2 diabetic mice. Int J Biol Sci 2015; 11:472-81. [PMID: 25798066 PMCID: PMC4366645 DOI: 10.7150/ijbs.10809] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/02/2015] [Indexed: 01/01/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance, oxidative stress, and obesity. The db/db mouse model displays increased levels of insulin resistance, obesity, and an over-accumulation of hepatic triglycerides, making it an excellent model for studying NAFLD. In db/db mice, intra-bone marrow-bone marrow transplantation plus thymus transplantation (IBM-BMT+TT) improves type 2 diabetes mellitus (T2 DM) by normalizing the T-cell imbalance. We hypothesized that this approach would improve Sirt1 expression in the liver and benefit liver development. The db/db mice were treated with IBM-BMT+TT, and plasma MCP-1, IL-6, adiponection, LDL, Sirt1, and HO-1 levels were then assessed. Stem cell transplantation decreased the levels of plasma inflammatory cytokines and LDL while it increased the expression of Sirt1 and HO-1, resulting in decreased progression of fatty liver. Moreover, Sirt1 and HO-1 expression were both detected in the thymus and many HO-1-positive cells were observed in the bone marrow. This is the first report of stem cell transplantation improving the antioxidant function in the liver, thymus, and bone marrow of db/db mice by increasing the levels of Sirt1 and HO-1. This approach may prove useful in the treatment of nonalcoholic steatohepatitis and its clinical manifestations.
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Affiliation(s)
- Ming Li
- 1. Department of Stem Cell Disorders, Kansai Medical University, Hirakata City, Osaka, Japan
| | - Kequan Guo
- 2. Department of Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, China
| | - Luca Vanella
- 3. Department of Drug Science, Section of Biochemistry, University of Catania, Catania, Italy
| | - Shigeru Taketani
- 4. Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan
| | - Yasushi Adachi
- 5. Division of Surgical Pathology, Toyooka Hospital, Hyogo, Japan
| | - Susumu Ikehara
- 1. Department of Stem Cell Disorders, Kansai Medical University, Hirakata City, Osaka, Japan
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Podrini C, Koffas A, Chokshi S, Vinciguerra M, Lelliott CJ, White JK, Adissu HA, Williams R, Greco A. MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis. FASEB J 2014; 29:1676-87. [PMID: 25526730 DOI: 10.1096/fj.14-262717] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/24/2014] [Indexed: 01/14/2023]
Abstract
The importance of epigenetic changes in the development of hepatic steatosis is largely unknown. The histone variant macroH2A1 under alternative splicing gives rise to macroH2A1.1 and macroH2A1.2. In this study, we show that the macroH2A1 isoforms play an important role in the regulation of lipid accumulation in hepatocytes. Hepatoma cell line and immortalized human hepatocytes transiently transfected or knocked down with macroH2A1 isoforms were used as in vitro model of fat-induced steatosis. Gene expressions were analyzed by quantitative PCR array and Western blot. Chromatin immunoprecipitation analysis was performed to check the association of histone H3 lysine 27 trimethylation (H3K27me3) and histone H3 lysine 4 trimethylation (H3K4me3) with the promoter of lipogenic genes. Livers from knockout mice that are resistant to lipid deposition despite a high-fat diet were used for histopathology. We found that macroH2A1.2 is regulated by fat uptake and that its overexpression caused an increase in lipid uptake, triglycerides, and lipogenic genes compared with macroH2A1.1. This suggests that macroH2A1.2 is important for lipid uptake, whereas macroH2A1.1 was found to be protective. The result was supported by a high positivity for macroH2A1.1 in knockout mice for genes targeted by macroH2A1 (Atp5a1 and Fam73b), that under a high-fat diet presented minimal lipidosis. Moreover, macroH2A1 isoforms differentially regulate the expression of lipogenic genes by modulating the association of the active (H3K4me3) and repressive (H3K27me3) histone marks on their promoters. This study underlines the importance of the replacement of noncanonical histones in the regulation of genes involved in lipid metabolism in the progression of steatosis.
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Affiliation(s)
- Christine Podrini
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Apostolos Koffas
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Shilpa Chokshi
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Manlio Vinciguerra
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Christopher J Lelliott
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Jacqueline K White
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Hibret A Adissu
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Roger Williams
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Azzura Greco
- *Foundation for Liver Research, Institute of Hepatology, London, United Kingdom; University College London (UCL)--Institute for Liver & Digestive Health, UCL Medical School, London, United Kingdom, Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and Physiology and Experimental Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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Zhou X, Zhu HQ, Ma CQ, Li HG, Liu FF, Chang H, Lu J. Two polymorphisms of USF1 gene (-202G>A and -844C>T) may be associated with hepatocellular carcinoma susceptibility based on a case-control study in Chinese Han population. Med Oncol 2014; 31:301. [PMID: 25367853 DOI: 10.1007/s12032-014-0301-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a prototype of liver cancer, which is closely related to manifested metabolism of lip and glucose. Upstream transcription factor 1 (USF1) is an important transcription factor in human genome, and it regulates the expression of multiple genes associated with lipid and glucose metabolism. This study aims at investigating the correlation between seven common USF1 polymorphisms (i.e., -1994 G>A, -202 G>A, 7998 A>G, -844 C>T, 9042 C>G, 9441 T>C, and -2083 G>A) and the risk of HCC. Elucidation of the interaction might be of vital importance to the diagnosis and prognosis of HCC. One hundred and fifty-five HCC patients and 160 healthy controls from a Chinese Han population were involved in this study. Tag single-nucleotide polymorphisms (SNPs) were identified with reference to CBI-dbSNP and HapMap databases. DNA was extracted from blood samples, and matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was conducted to determine the polymorphisms of USF1. Odds ratio (OR) and 95% confidence interval were applied to evaluate the difference of genotype distribution. Seven SNPs were selected to be representatives. No significant difference was observed concerning -1994 G>A, 7998 A>G, 9042 C>G, 9441 T>C, and -2083 G>A polymorphisms (all P > 0.05). A significantly elevated genotype frequency regarding -202 G>A polymorphism was observed in HCC patients [AA vs. GG: OR 2.13 (1.13-4.01), P = 0.019; AA vs. GG+GA: OR 2.22 (1.32-3.75), P = 0.003; A allele vs. G allele: OR 1.46 (1.07-2.01), P = 0.018]. Subjects carrying mutant -844 C>T genotypes also had a higher risk of HCC [CT vs. CC: OR 1.88 (1.17-3.04), P = 0.009; CT+TT vs. CC: OR 1.83 (1.17-2.86), P = 0.008; T allele vs. C allele: OR 1.49 (1.06-2.09), P = 0.020]. Further studies are recommended to validate our findings in different ethnicity and to clarify the functional relationship between USF1 polymorphisms and the susceptibility of HCC.
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Affiliation(s)
- Xu Zhou
- Department of Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University (East District), No. 9677 Jingshi Road, Jinan, 250014, Shandong Province, China
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Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:637027. [PMID: 25371775 PMCID: PMC4211163 DOI: 10.1155/2014/637027] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.
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