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Wu Y, Yu J, Song H, Lu D, Li Z, Li X, Ding Z, Zhou L, Ma J, Zhang Y, Li Y. Profiling of RNA N6-Methyladenosine methylation reveals the critical role of m6A in betaine alleviating hepatic steatosis. Sci Rep 2025; 15:7298. [PMID: 40025137 PMCID: PMC11873031 DOI: 10.1038/s41598-025-91573-0] [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: 08/19/2024] [Accepted: 02/21/2025] [Indexed: 03/04/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major predisposing factor of metabolic dysfunction-associated steatohepatitis, hepatic fibrosis and hepatocellular carcinoma. Abnormal RNA m6A modification leads to the disturbance of lipid metabolism, insulin resistance, and chronic inflammation, all of which are critical for the onset and progression of MASLD. It has been shown that betaine supplementation has an ameliorative effect on symptoms associated with MASLD. The purpose of this study is to explore the role of RNA m6A modification in the alleviation of MASLD by betaine, and to find out the possible targets of betaine. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were respectively employed to contrast m6A methylation profiles of livers from high-fat diet mice with betaine supplementation vs. those without betaine supplementation (HB vs. HFD). Functional enrichment analysis showed that up-methylated genes are mainly related to mTOR signaling pathway, Rap1 signaling pathway and MAPK signaling pathway. In addition, differentially expressed mRNAs were enriched in pathways such as promoting lipid catabolism and reducing lipid accumulation. By combining analyses of MeRIP-seq and RNA-seq, we identified 27 genes exhibiting significant differences in m6A abundance and mRNA levels. Notably, a new candidate gene, Trub2, was screened out and identified. Inhibition of Trub2 increased intracellular TG levels in AML12 cells, and this promotion was reduced by betaine, suggesting that betaine reduces intracellular TG levels by increasing Trub2 expression. Our findings in this study provide a new target and a new approach for the treatment of MASLD.
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Affiliation(s)
- Yuna Wu
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Jingsu Yu
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Haisen Song
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Dehao Lu
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Zhilin Li
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Xiangling Li
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Zhaoxuan Ding
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Lei Zhou
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Jie Ma
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China
| | - Ying Zhang
- School of Life Sciences, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - Yixing Li
- Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, 530004, China.
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Liu Y, Fan Y, Liu J, Liu X, Li X, Hu J. Application and mechanism of Chinese herb medicine in the treatment of non-alcoholic fatty liver disease. Front Pharmacol 2024; 15:1499602. [PMID: 39605910 PMCID: PMC11598537 DOI: 10.3389/fphar.2024.1499602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition closely associated with metabolic syndrome, with its incidence rate continuously rising globally. Recent studies have shown that the development of NAFLD is associated with insulin resistance, lipid metabolism disorder, oxidative stress and endoplasmic reticulum stress. Therapeutic strategies for NAFLD include lifestyle modifications, pharmacological treatments, and emerging biological therapies; however, there is currently no specific drug to treat NAFLD. However Chinese herb medicine (CHM) has shown potential in the treatment of NAFLD due to its unique therapeutic concepts and methods for centuries in China. This review aims to summarize the pathogenesis of NAFLD and some CHMs that have been shown to have therapeutic effects on NAFLD, thus enriching the scientific connotation of TCM theories and facilitating the exploration of TCM in the treatment of NAFLD.
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Affiliation(s)
- Yuqiao Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Fan
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jibin Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyang Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiuyan Li
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingqing Hu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Xin-Huangpu Joint Innovation Institute of Chinese Medicine, Guangzhou, China
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Cai W, Wu S, Ming X, Li Z, Pan D, Yang X, Yang M, Yuan Y, Chen X. IL6 Derived from Macrophages under Intermittent Hypoxia Exacerbates NAFLD by Promoting Ferroptosis via MARCH3-Led Ubiquitylation of GPX4. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402241. [PMID: 39229924 PMCID: PMC11538716 DOI: 10.1002/advs.202402241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/24/2024] [Indexed: 09/05/2024]
Abstract
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA-related NAFLD using clinical data analyses, cell-based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA-seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co-IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer-1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH-induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD.
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Affiliation(s)
- Weisong Cai
- Department of OtorhinolaryngologyHead and Neck SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Sleep Medicine CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Sa Wu
- Department of Gynaecology IIMaternal and Child Health Hospital of Hubei ProvinceTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430070China
| | - Xiaoping Ming
- Department of OtorhinolaryngologyHead and Neck SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Sleep Medicine CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Bariatric and Metabolic Disease Surgery CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Dingyu Pan
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Bariatric and Metabolic Disease Surgery CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Xiuping Yang
- Department of OtorhinolaryngologyHead and Neck SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Sleep Medicine CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Minlan Yang
- Department of OtorhinolaryngologyHead and Neck SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Sleep Medicine CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Bariatric and Metabolic Disease Surgery CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Xiong Chen
- Department of OtorhinolaryngologyHead and Neck SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
- Sleep Medicine CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
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Wu CY, Chen Y, Chen MT, Fu TT, Liu J, Liu FF, Xu CJ, Li WS, Li BL, Jiang ZP, Rao Y, Huang L. Natural linoleic acid from marine fungus Eutypella sp. F0219 blocks KEAP1/NRF2 interaction and ameliorates MASLD by targeting FABP4. Free Radic Biol Med 2024; 224:630-643. [PMID: 39299527 DOI: 10.1016/j.freeradbiomed.2024.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/28/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024]
Abstract
Ectopic lipid accumulation induced lipotoxicity plays a crucial role in exacerbating the development of metabolic dysfunction-associated steatotic liver disease (MASLD), which affects over 30 % of the worldwide population and 85 % of the obese population. The growing demand for effective therapeutic agents highlights the need for high-efficacy lipotoxicity ameliorators and relevant therapeutic targets in the fight against MASLD. This study aimed to discover natural anti-lipotoxic and anti-MASLD candidates and elucidate the underlying mechanism and therapeutic targets. Utilizing palmitic acid (PA)-induced HepG-2 and primary mouse hepatocyte models, we identified linoleic acid (HN-002), a ligand of fatty acid binding protein 4 (FABP4), from the marine fungus Eutypella sp. F0219. HN-002 dose-dependently prevented lipid overload-induced hepatocyte damage and lipid accumulation, inhibited fatty acid esterification, and ameliorated oxidative stress. These beneficial effects were associated with improvements in mitochondrial adaptive oxidation. HN-002 treatment enhanced lipid transport into mitochondria and oxidation, inhibited mitochondrial depolarization, and reduced mitochondrial ROS (mtROS) level in PA-treated hepatocytes. Mechanistically, HN-002 treatment disrupted the interaction between KEAP1 and NRF2, leading to NRF2 deubiquitylation and nuclear translocation, which activated beneficial metabolic regulation. In vivo, HN-002 treatment (20 mg/kg/per 2 days, i. p.) for 25 days effectively reversed hepatic steatosis and liver injury in the fast/refeeding plus high-fat/high-cholesterol diet induced MASLD mice. These therapeutic effects were associated with enhanced mitochondrial adaptive oxidation and activation of NRF2 signaling in the liver. These data suggest that HN-002 would be an interesting candidate for MASLD by improving mitochondrial oxidation via the FABP4/KEAP1/NRF2 axis. The discovery offers new insights into developing novel anti- MASLD agents derived from marine sources.
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Affiliation(s)
- Chen-Yan Wu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Yue Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Meng-Ting Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Ting-Ting Fu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Jin Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Fei-Fei Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Cong-Jun Xu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Wan-Shan Li
- Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, China
| | - Bao-Li Li
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China
| | - Zhong-Ping Jiang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China.
| | - Yong Rao
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China.
| | - Ling Huang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China.
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Ma X, Zou H, Zhan J, Gao J, Xie Y. Assessment of the clinical value of five noninvasive predictors of metabolic dysfunction-associated steatotic liver disease in Han Chinese adults. Eur J Gastroenterol Hepatol 2024; 36:1209-1219. [PMID: 38973526 DOI: 10.1097/meg.0000000000002806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
BACKGROUND Fatty Liver Index (FLI), Triglyceride-Glucose Index (TyG), Lipid Accumulation Product (LAP), Zhejiang University Index (ZJU), and Visceral Adiposity Index (VAI) are five classical predictive models for fatty liver disease. Our cross-sectional study aimed to identify the optimal predictors by comparing the predictive value of five models for metabolic dysfunction-associated steatotic liver disease (MASLD) risk. METHODS Data on 2687 participants were collected from West China Hospital of Sichuan University. Controlled attenuation parameters assessed by transient elastography were used to effectively diagnose MASLD. Logistic regression analysis was used to estimate the odd ratios and 95% confidence intervals between indices and MASLD risk. Receiver operating characteristic curves were plotted to evaluate the predictive value of indices. RESULTS This study included 1337 normal and 1350 MASLD samples. The average age of MASLD patients is 47 years old, and the prevalence was higher in males (39.3%) than in females (10.9%). Five indices were positively correlated with MASLD risk, with the strongest correlation for TyG. Overall, the area under the curve of the indicators was: ZJU 0.988, FLI 0.987, LAP 0.982, TyG 0.942, and VAI 0.941. In the gender stratification, ZJU (0.989) performed best in males. FLI (0.988) and ZJU (0.987) had similar predictive ability in females. In the age stratification, FLI performed better in predicting the middle-aged group aged 30-40 years (0.991). CONCLUSION For Chinese Han adults, ZJU is the best predictive index for initial screening of MASLD. FLI can serve as an alternative tool for ZJU to predict females.
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Affiliation(s)
- Xiaopu Ma
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Yan Y, Yuan H, Yang F, Na H, Yu X, Liu J, Wang Y. Seabuckthorn polysaccharides mitigate hepatic steatosis by modulating the Nrf-2/HO-1 pathway and gut microbiota. AMB Express 2024; 14:100. [PMID: 39251509 PMCID: PMC11383914 DOI: 10.1186/s13568-024-01756-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming a significant global public health threat. Seabuckthorn (Hippophae rhamnoides L.) has been used in traditional Chinese medicine (TCM). The hypolipidemic effects of Seabuckthorn polysaccharides (SP) against high-fat diets (HFD)-induced NAFLD were systematically explored and compared with that of Bifidobacterium lactis V9 (B. Lactis V9). Results showed that HFD-induced alanine transaminase (ALT) and aspartate aminotransferase (AST) levels decreased by 2.8-fold and 4.5-fold, respectively, after SP supplementation. Moreover, the alleviating effect on hepatic lipid accumulation is better than that of B. Lactis V9. The ACC and FASN mRNA levels were significantly reduced by 1.8 fold (P < 0.05) and 2.3 folds (P < 0.05), respectively, while the CPT1α and PPARα mRNA levels was significantly increased by 2.3 fold (P < 0.05) and 1.6 fold (P < 0.05), respectively, after SP administration. SP activated phosphorylated-AMPK and inhibited PPARγ protein expression, improved serum oxidative stress and inflammation (P < 0.05). SP supplementation leads to increased hepatic expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and Superoxide dismutase-2 (SOD-2). Furthermore, SP treatment improved HFD-induced intestinal dysbiosis. Lentisphaerae, Firmicutes, Tenericutes and Peptococcus sp., RC9_gut_group sp., and Parabacteroides sp. of the gut microbiota were significantly associated with hepatic steatosis and indicators related to oxidative stress and inflammation. Therefore, SP can mitigate hepatic lipid accumulation by regulating Nrf-2/HO-1 signaling pathways and gut microbiota. This study offers new evidence supporting the use of SP as a prebiotic treatment for NAFLD.
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Affiliation(s)
- Yan Yan
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Haisheng Yuan
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Fan Yang
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Heiya Na
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Xiuling Yu
- Inner Mongolia Tianqi Biotechnology Co., Ltd, Chifeng, 024000, China
| | - Jingran Liu
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China.
| | - Yuzhen Wang
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China.
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Saeed M, Shoaib A, Tasleem M, Al-Shammary A, Kausar MA, El Asmar Z, Abdelgadir A, Sulieman AME, Ahmed EH, Zahin M, Ansari IA. Role of Alkannin in the Therapeutic Targeting of Protein-Tyrosine Phosphatase 1B and Aldose Reductase in Type 2 Diabetes: An In Silico and In Vitro Evaluation. ACS OMEGA 2024; 9:36099-36113. [PMID: 39220541 PMCID: PMC11359625 DOI: 10.1021/acsomega.4c00082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024]
Abstract
Alkannin is a plant-derived naphthoquinone that is isolated from the Boraginaceae family plants. In our previous studies, we found that shikonin, which is the R-enantiomer of alkannin, has potent antidiabetic activity by inhibiting the action of the aldose reductase (AR) enzyme and the protein-tyrosine phosphatase 1B (PTP1B). Therefore, in this study, we aim to explore the antidiabetic effect of alkannin targeting PTP1B and AR by employing in silico and in vitro techniques. For in silico, we used different parameters such as ADMET analysis, molecular docking, MD simulation, Root Mean Square Deviation (RMSD), protein-ligand mapping, and free binding energy calculation. The in vitro evaluation was done by assessing the inhibitory activity and enzyme kinetics of PTP1B and AR inhibition by alkannin. The in silico studies indicate that alkannin possesses favorable pharmacological properties and possesses strong binding affinity for diabetes target proteins. Hydrogen bonds (Val297, Ala299, Leu300, and Ser302) and hydrophobic interactions (Trp20, Val47, Tyr48, Trp79, Trp111, Phe122, Trp219, Val297, Cys298, Ala299, Leu300, and Leu301) are established by the compound, which potentially improves specificity and aids in the stabilization of the protein-ligand complex. The results from in vitro studies show a potent dose-dependent PTP1B inhibitory activity with an IC50 value of 19.47 μM, and toward AR it was estimated at 22.77 μM. Thus, from the results it is concluded that a low IC50 value of alkannin for both PTP1B and AR along with favorable pharmacological properties and optimal intra-molecular interactions indicates its utilization as a potential drug candidate for the management of diabetes and its end complications.
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Affiliation(s)
- Mohd Saeed
- Department
of Biology, College of Sciences, University
of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Ambreen Shoaib
- Department
of Clinical Pharmacy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Munazzah Tasleem
- Center
for Global Health Research, Saveetha Medical
College and Hospital, Chennai 602105, India
| | - Asma Al-Shammary
- Department
of Public Health, College of Public Health and Health Informatics, University of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Mohd Adnan Kausar
- Department
of Biochemistry, College of Medicine, University
of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Zeina El Asmar
- Department
of Biology, College of Sciences, University
of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Abdelmuhsin Abdelgadir
- Department
of Biology, College of Sciences, University
of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Abdel Moneim E. Sulieman
- Department
of Biology, College of Sciences, University
of Ha’il, P.O. Box 2240, Ha’il 81451, Saudi Arabia
| | - Enas Haridy Ahmed
- University
of Ha’il, Faculty of Medicine
Anatomy Department, Ha’il, KSA, Ain Shams University, Faculty
of Medicine Anatomy and Embryology Department, Cairo 11566, Egypt
| | - Maryam Zahin
- James
Graham
Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, United States
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Zhu W, Hong Y, Tong Z, He X, Li Y, Wang H, Gao X, Song P, Zhang X, Wu X, Tan Z, Huang W, Liu Z, Bao Y, Ma J, Zheng N, Xie C, Ke X, Zhou W, Jia W, Li M, Zhong J, Sheng L, Li H. Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation. Cell Rep Med 2024; 5:101477. [PMID: 38508143 PMCID: PMC10983109 DOI: 10.1016/j.xcrm.2024.101477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 12/10/2023] [Accepted: 02/21/2024] [Indexed: 03/22/2024]
Abstract
Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.
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Affiliation(s)
- Weize Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Hong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhaowei Tong
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Xiaofang He
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinxin Gao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Pengtao Song
- Department of Pathology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Xianshan Zhang
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Xiaochang Wu
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Zhenhua Tan
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Wenjin Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zekun Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yiyang Bao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junli Ma
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ningning Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cen Xie
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xisong Ke
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Wen Zhou
- Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural, Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China
| | - Mingxiao Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jing Zhong
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China.
| | - Lili Sheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Houkai Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Yan R, Cai H, Zhou X, Bao G, Bai Z, Ge RL. Hypoxia-inducible factor-2α promotes fibrosis in non-alcoholic fatty liver disease by enhancing glutamine catabolism and inhibiting yes-associated protein phosphorylation in hepatic stellate cells. Front Endocrinol (Lausanne) 2024; 15:1344971. [PMID: 38501098 PMCID: PMC10946064 DOI: 10.3389/fendo.2024.1344971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/25/2024] [Indexed: 03/20/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence and affects approximately one-third of adults, owing to high-fat dietary habits and a sedentary lifestyle. The role of hypoxia-inducible factor 2α (HIF-2α) in NAFLD progression remains unknown. This study aimed to investigate the effects of chronic hypoxia on NAFLD progression by examining the role of hypoxia-inducible factor 2α (HIF-2α) activation and that of hepatic stellate cell (HSC)-derived myofibroblasts through glutaminolysis. We hypothesised that hypoxia exacerbates NAFLD by promoting HIF-2α upregulation and inhibiting phosphorylated yes-associated protein (YAP), and that increasing YAP expression enhances HSC-derived myofibroblasts. We studied patients with NAFLD living at high altitudes, as well as animal models and cultured cells. The results revealed significant increases in HSC-derived myofibroblasts and collagen accumulation caused by HIF-2α and YAP upregulation, both in patients and in a mouse model for hypoxia and NAFLD. HIF-2α and HIF-2α-dependent YAP downregulation reduced HSC activation and myofibroblast levels in persistent chronic hypoxia. Furthermore, hypoxia-induced HIF-2α upregulation promoted YAP and inhibited YAP phosphorylation, leading to glutaminase 1 (GLS1), SLC38A1, α-SMA, and Collagen-1 overexpression. Additionally, hypoxia restored mitochondrial adenosine triphosphate production and reactive oxygen species (ROS) overproduction. Thus, chronic hypoxia-induced HIF-2α activation enhances fibrosis and NAFLD progression by restoring mitochondrial ROS production and glutaminase-1-induced glutaminolysis, which is mediated through the inhibition of YAP phosphorylation and increased YAP nuclear translocation. In summary, HIF-2α plays a pivotal role in NAFLD progression during chronic hypoxia.
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Affiliation(s)
- Ranran Yan
- Qinghai-Utah Joint Key Lab for High-altitude Medicine, Medical College of Qinghai University, Xining, China
- Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, China
- Key Laboratory of High-Altitude Medicine in Qinghai University, Ministry of Education, Xining, China
- Key Laboratory for Application of High-Altitude Medicine in Qinghai Province, Xining, China
| | - Hao Cai
- Oncology Department, The Fifth People’s Hospital of Qinghai Provincial, Xining, China
| | - Xiaofeng Zhou
- Affiliated Hospital of Qinghai University, Xining, China
| | - Guodan Bao
- Qinghai-Utah Joint Key Lab for High-altitude Medicine, Medical College of Qinghai University, Xining, China
- Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, China
- Key Laboratory of High-Altitude Medicine in Qinghai University, Ministry of Education, Xining, China
- Affiliated Hospital of Qinghai University, Xining, China
| | - Zhenzhong Bai
- Qinghai-Utah Joint Key Lab for High-altitude Medicine, Medical College of Qinghai University, Xining, China
- Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, China
- Key Laboratory of High-Altitude Medicine in Qinghai University, Ministry of Education, Xining, China
- Key Laboratory for Application of High-Altitude Medicine in Qinghai Province, Xining, China
| | - Ri-li Ge
- Qinghai-Utah Joint Key Lab for High-altitude Medicine, Medical College of Qinghai University, Xining, China
- Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, China
- Key Laboratory of High-Altitude Medicine in Qinghai University, Ministry of Education, Xining, China
- Key Laboratory for Application of High-Altitude Medicine in Qinghai Province, Xining, China
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10
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Yang Z, Xiong Z, Wang Q, Zhou N. A bibliometric analysis of macrophages associated with non-alcoholic fatty liver disease research from 2005 to 2023. Heliyon 2024; 10:e24187. [PMID: 38293366 PMCID: PMC10827458 DOI: 10.1016/j.heliyon.2024.e24187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition associated with the risk of progressing to decompensated cirrhosis and hepatocellular carcinoma. While macrophages play a crucial role in the development of NAFLD, their heterogeneity and plasticity allow them to undertake diverse roles in immune response, tissue repair, and maintaining tissue homeostasis. Thus, the exact involvement of macrophages in the onset and progression of NAFLD remains to be further explored. This study aims to employ bibliometric analysis to elucidate the role of macrophages in the pathogenesis of NAFLD, analyze research focal points in this domain, and speculate on future research trends. The literature search, conducted using the Web of Science Core Collection, encompassed articles and reviews related to macrophages and NAFLD published between 2005 and 2023. A bibliometric analysis of 1264 extracted publications was performed using VOSviewer 1.6.17 and Citespace 6.1. R2, evaluating parameters such as spatial and temporal distribution, authors, thematic categories, topic distribution, references, and keywords. The findings revealed a steady global increase in publications in this field, with the United States contributing the most followed by China. The University of California System produced the highest volume of publications, while the Journal of Hepatology had the highest impact factors among the top 10 publishing journals. Tacke Frank emerged as both the most prolific author and the most cited. Co-occurrence and burst analysis of keywords and references highlighted the hotspots in this research area, emphasizing the mechanisms of NAFLD pathogenesis, metabolic regulation, immune modulation, and oxidative stress. Maintaining hepatic homeostasis by liver macrophages and macrophage polarization were identified as trending research directions in this field. Based on the bibliometric analysis, continued attention toward NAFLD therapeutic research involving hepatic macrophages is anticipated. As the mechanisms underlying NAFLD pathogenesis are further elucidated, the development of more treatment approaches related to macrophage immunology and metabolic regulation may expand therapeutic options. This study offers valuable insights into the current state and future trends in the field, providing beneficial guidance to researchers aiming to make significant contributions.
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Affiliation(s)
- Zhen Yang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiuguo Wang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ning Zhou
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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11
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Nagai K, Nagai K, Iwaki M, Kobayashi T, Nogami A, Oka M, Saito S, Yoneda M. Frontiers of Collaboration between Primary Care and Specialists in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Review. Life (Basel) 2023; 13:2144. [PMID: 38004284 PMCID: PMC10672694 DOI: 10.3390/life13112144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common liver disease. It has a rapidly growing patient population owing to the increasing prevalence of obesity and type 2 diabetes. Patients with MASLD are primarily treated by family physicians when fibrosis is absent or mild and by gastroenterologists/hepatologists when fibrosis is more advanced. It is imperative that a system for the appropriate treatment and surveillance of hepatocellular carcinoma be established in order to ensure that highly fibrotic cases are not overlooked among the large number of MASLD patients. Family physicians should check for viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and drug-induced liver disease, and should evaluate fibrosis using NIT; gastroenterologists/hepatologists should perform liver biopsy, ultrasound elastography (260 units in Japan as of October 2023), and MR elastography (35 units in Japan as of October 2023). This review presents the latest findings in MASLD and the role, accuracy, and clinical use of NIT. It also describes the collaboration between Japanese primary care and gastroenterologists/hepatologists in Japan in the treatment of liver diseases, including MASLD.
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Affiliation(s)
- Koki Nagai
- Gastroenterology Division, National Hospital Organization Yokohama Medical Center, 3-60-2 Harajyuku, Totsuka-ku, Yokohama 245-8575, Japan;
| | - Kazuki Nagai
- Nagai Clinic, 1-7-25 Yokodai, Isogo-ku, Yokohama 235-0045, Japan;
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Masanao Oka
- OkaMedical, 1-19-18-3F Kamiookanishi, Kounan-ku, Yokohama 233-0002, Japan;
| | - Satoru Saito
- Sanno Hospital, 8-10-16 Akasaka, Minato-ku, Tokyo 107-0052, Japan;
| | - Masato Yoneda
- Gastroenterology Division, National Hospital Organization Yokohama Medical Center, 3-60-2 Harajyuku, Totsuka-ku, Yokohama 245-8575, Japan;
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12
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Jin R, Juventus Aweya J, Lin R, Weng W, Shang J, Wang D, Fan Y, Yang S. The bioactive peptide VLATSGPG regulates the abnormal lipid accumulation and inflammation induced by free fatty acids in HepG2 cells via the PERK signaling pathway. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2023] Open
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13
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Govaere O, Anstee QM. Non-Alcoholic Fatty Liver Disease and Steatohepatitis. ENCYCLOPEDIA OF CELL BIOLOGY 2023:610-621. [DOI: 10.1016/b978-0-12-821618-7.00265-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Bukke VN, Moola A, Serviddio G, Vendemiale G, Bellanti F. Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease. World J Gastroenterol 2022; 28:6909-6921. [PMID: 36632321 PMCID: PMC9827579 DOI: 10.3748/wjg.v28.i48.6909] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/05/2022] [Accepted: 11/23/2022] [Indexed: 12/26/2022] Open
Abstract
Oxidative stress is a key driver in the development and progression of several diseases, including metabolic associated fatty liver disease (MAFLD). This condition includes a wide spectrum of pathological injuries, extending from simple steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD, progressing to liver fibrosis and cirrhosis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of redox homeostasis. NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant, anti-inflammatory, and cytoprotective response. Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD deve-lopment, from simple steatosis to inflammation, advanced fibrosis, and ini-tiation/progression of hepatocellular carcinoma. NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes. Thus, modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies. This review outlined the current knowledge on the effects of NRF2 pathway, modulators, and mechanisms involved in the therapeutic implications of liver steatosis, inflammation, and fibrosis in MAFLD.
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Affiliation(s)
- Vidyasagar Naik Bukke
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Archana Moola
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
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15
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Sheng W, Ji G, Zhang L. Management of non-alcoholic fatty liver disease patients with sleep apnea syndrome. World J Gastroenterol 2022; 28:6099-6108. [PMID: 36483151 PMCID: PMC9724487 DOI: 10.3748/wjg.v28.i43.6099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/20/2022] [Accepted: 11/06/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with sleep apnea syndrome (SAS). Many NAFLD patients have SAS, and obstructive sleep apnea hypopnea syndrome is also considered to be an independent risk factor for NAFLD, as it contributes to the progression of NAFLD via oxidative stress, lipid peroxidation, inflammation, and insulin resistance. This review aims to provide some recommendations for the management of NAFLD patients with SAS, including diet, exercise, weight loss, and continuous positive airway pressure. This review also highlights the importance of effective strategies in NAFLD prevention and treatment.
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Affiliation(s)
- Wei Sheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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16
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Role of Oxidative Stress and Lipid Peroxidation in the Pathophysiology of NAFLD. Antioxidants (Basel) 2022; 11:antiox11112217. [PMID: 36358589 PMCID: PMC9686676 DOI: 10.3390/antiox11112217] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterised by an excess of hepatic fat that can progress to steatohepatitis, fibrosis, cirrhosis and hepatocarcinoma. The imbalance between lipid uptake/lipogenesis and lipid oxidation/secretion in the liver is a major feature of NAFLD. Given the lack of a non-invasive and reliable methods for the diagnosis of non-alcoholic steatohepatitis (NASH), it is important to find serum markers that are capable of discriminating or defining patients with this stage of NASH. Blood samples were obtained from 152 Caucasian subjects with biopsy-proven NAFLD due to persistently elevated liver enzyme levels. Metabolites representative of oxidative stress were assessed. The findings derived from this work revealed that NAFLD patients with a NASH score of ≥ 4 showed significantly higher levels of lipid peroxidation (LPO). Indeed, LPO levels above the optimal operating point (OOP) of 315.39 μM are an independent risk factor for presenting a NASH score of ≥ 4 (OR: 4.71; 95% CI: 1.68−13.19; p = 0.003). The area under the curve (AUC = 0.81, 95% CI = 0.73−0.89, p < 0.001) shows a good discrimination ability of the model. Therefore, understanding the molecular mechanisms underlying the basal inflammation present in these patients is postulated as a possible source of biomarkers and therapeutic targets in NASH.
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17
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Bathish B, Robertson H, Dillon JF, Dinkova-Kostova AT, Hayes JD. Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2. Free Radic Biol Med 2022; 188:221-261. [PMID: 35728768 DOI: 10.1016/j.freeradbiomed.2022.06.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.
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Affiliation(s)
- Boushra Bathish
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Holly Robertson
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
| | - John F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - John D Hayes
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK.
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18
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Wang L, Cao ZM, Zhang LL, Li JM, Lv WL. The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective. Front Immunol 2022; 13:923599. [PMID: 35911738 PMCID: PMC9326173 DOI: 10.3389/fimmu.2022.923599] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota is a microecosystem composed of various microorganisms. It plays an important role in human metabolism, and its metabolites affect different tissues and organs. Intestinal flora maintains the intestinal mucosal barrier and interacts with the immune system. The liver is closely linked to the intestine by the gut-liver axis. As the first organ that comes into contact with blood from the intestine, the liver will be deeply influenced by the gut microbiota and its metabolites, and the intestinal leakage and the imbalance of the flora are the trigger of the pathological reaction of the liver. In this paper, we discuss the role of gut microbiota and its metabolites in the pathogenesis and development of autoimmune liver diseases((including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), metabolic liver disease such as non-alcoholic fatty liver disease, cirrhosisits and its complications, and liver cancer from the perspective of immune mechanism. And the recent progress in the treatment of these diseases was reviewed from the perspective of gut microbiota.
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Affiliation(s)
- Li Wang
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | - Zheng-Min Cao
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | | | - Juan-mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen-liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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19
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Mulberry Leaf Flavonoids Inhibit Liver Inflammation in Type 2 Diabetes Rats by Regulating TLR4/MyD88/NF-κB Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3354062. [PMID: 35845591 PMCID: PMC9279020 DOI: 10.1155/2022/3354062] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/17/2022]
Abstract
The incidence of liver-related complications in type 2 diabetes mellitus (T2DM) is rapidly increasing, which affects the physical and mental health of T2DM patients. Mulberry leaf flavonoids (MLF) were confirmed to have certain effects on lowering blood glucose and anti-inflammation. In this study, the high-fat diet (HFD) + STZ method was used to establish T2DM rat model and the MLF was administered by gavage for eight weeks. During the experiment, body weight and blood glucose level were measured at different time points. The pathological changes of rat liver were observed by H&E staining. The serum glucolipid metabolic indicators of serum, fasting insulin (FINS), and inflammatory factors levels were detected by ELISA. The expression levels of toll-like receptor 4 (TLR4), TNF receptor-associated factor 6 (TRAF6), myeloid differentiation factor 88 (MyD88), inhibitor of NF-κB alpha (IκΒα), p-IκΒα, and nuclear factor kappa-B (NF-κB)/p65 protein in liver tissue were measured by Western Blot. After 8 weeks' MLF treatment, the blood glucose of rats showed a downward trend; glycolipid metabolism level and insulin resistance were improved, which suggested that MLF could improve the disorder of glucose and lipid metabolism. The pathological damage and inflammation of the liver in T2DM rats were significantly improved, the levels of related serum inflammatory factors were reduced, and the expression of liver tissue-related proteins was downregulated. Our results indicated that MLF could reduce blood glucose and inhibit the development of liver inflammation. The mechanisms may be associated with the activation of TLR4/MyD88/NF-κB signal pathway to reduce the levels of inflammatory factors in serum.
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20
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Al Mutori H, Al Rudaini M, Omar AF, Anwar S, Selim Y, Yaseen B. Nonalcoholic Fatty Liver Disease Among Obese Patients in Oman. BIONATURA 2022. [DOI: 10.21931/rb/2022.07.02.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Studies characterizing Nonalcoholic Fatty Liver Disease (NAFLD) are limited in Oman. This study aims to assess the prevalence of NAFLD in obese Omani patients and find its relationship with other obesity-related medical conditions. Fifty-five adult obese patients were evaluated via medical history, clinical examination, and laboratory tests. Patients with any possible risk of liver injury were excluded. Diagnosis of NAFLD relied on ultrasonography criteria. Data were entered and analyzed in SPSS (version 22). The prevalence of NAFLD was calculated using frequency and percentages. Out of the total patient population, 37 (67.3%) have had NAFLD. Most of the patients (81%) were below 50 years of age. Systolic hypertension was present in 45.9%, while diastolic hypertension was present in 43.2%. AST and ALT levels were significantly increased (p<0.001) in most patients; 81.1% and 73%, respectively. Fasting blood sugar (FBS) and glycosylated hemoglobin (HbA1c) levels were higher in NAFLD patients (p<0.01). Mean levels of LDL, uric acid, and total cholesterol were significantly higher in the NAFLD patients (p<0.01). In conclusion, NAFLD and related metabolic complications are prevalent in obese Omani individuals.
Keywords. NAFLD, Obesity, Oman
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Affiliation(s)
- Hamdi Al Mutori
- Department of Medicine, National University of Science and Technology, College of Medicine, Oman
| | - Mazin Al Rudaini
- Department of Medicine, National University of Science and Technology, College of Medicine, Oman
| | | | - Sanam Anwar
- Department of Public Health, National University of Science and Technology, College of Medicine
| | | | - Bahaa Yaseen
- Department of Gastroenterology, Aster Hospital, Oman
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21
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Han L, Zhang Y, Yue C, Huang Y, Wu Y, Chen J. Preliminary Study on Risk Factors for Morbidity of Nonalcoholic Fatty Liver Disease in High-Income Male Population. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:9331284. [PMID: 35251583 PMCID: PMC8890829 DOI: 10.1155/2022/9331284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/29/2021] [Accepted: 12/14/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Believed to be a result of metabolic syndrome and unhealthy lifestyle, the incidence of nonalcoholic fatty liver disease (NAFLD) has become a serious public health problem. Among the high-income male population, metabolic syndrome and unhealthy lifestyle are particularly prominent. Therefore, we conducted a survey on 375 high-income male subjects, expecting to understand the risk factors and related factors for morbidity of NAFLD among the high-income male population being physically examined in Shanghai. METHODS A cross-sectional study was applied to 375 high-income male subjects (including 190 patients with NAFLD and 185 non-NAFLD subjects) who were examined in the special needs clinic at Huadong Hospital affiliated to Fudan University. In combination with medical history, physical examination, and laboratory test results and by use of a self-made NAFLD health questionnaire, the basic data of the research objects were collected and the obtained data were subject to a correlation analysis. RESULTS This study investigated 375 high-income males, and the morbidity rate of NAFLD was 50.67%. The NAFLD group was higher than the non-NAFLD group in terms of body weight, BMI, systolic blood pressure, and diastolic blood pressure (P < 0.05). Hypertension (OR = 2.944), diabetes (OR = 7.278), and hyperuricemia (OR = 1.922) are the risk factors for NAFLD; compared with no metabolic diseases, one (OR = 1.848), two (OR = 2.417), and three metabolic diseases (OR = 14.788) are risk factors for the development of NAFLD. Compared with the non-NAFLD group, the NAFLD group had a higher level of WBC, RBC, Hb, PLT, FPG, HbA1c, ALT, AST, GGT, ALP, TP, and UA (P < 0.05). There was a statistically significant difference in the intake of supper and staple foods between the NAFLD group and the non-NAFLD group, and the highly greasy diet was a risk factor for NAFLD (OR = 2.173) as opposed to the nongreasy diet. CONCLUSION High-income male population is a high-risk group of NAFLD. Most of the patients with NAFLD have abnormal biochemical indicators as opposed to the healthy population and are more likely to be complicated with other chronic diseases or abnormal health status. And the occurrence of hypertension, diabetes, and hyperuricemia is the risk factor for the development of NAFLD. At the same time, the number of metabolic diseases complicated is also a risk factor for NAFLD as compared with the absence of complications with such metabolic diseases. Compared with a diet that is not greasy, the fact that high-income male NAFLD patients have a very greasy diet increases the risk of NAFLD.
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Affiliation(s)
- Li Han
- Huadong Hospital Affiliated to Fudan University, Department of Traditional Chinese Medicine, 221 Yan'an West Road,Jing'an District, Shanghai 200040, China
| | - Yuting Zhang
- Huadong Hospital Affiliated to Fudan University, Department of Digestion, 221 Yan'an West Road,Jing'an District, Shanghai 200040, China
| | - Cui Yue
- The Office of Good Clinical Practice, 221 West Yan'an Road, Huadong Hospital, Shanghai 200040, China
| | - Yiqin Huang
- Huadong Hospital Affiliated to Fudan University, Department of Digestion, 221 Yan'an West Road,Jing'an District, Shanghai 200040, China
| | - Yumin Wu
- Huadong Hospital Affiliated to Fudan University, Department of Nephrology, 221 Yan'an West Road,Jing'an District, Shanghai 200040, China
| | - Jie Chen
- Huadong Hospital Affiliated to Fudan University, Department of Geriatrics, 317 Room,168 Yan'an West Road,Jing'an District, Shanghai 200040, China
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Yang X, Deng Y, Tu Y, Feng D, Liao W. Nobiletin mitigates NAFLD via lipophagy and inflammation. Food Funct 2022; 13:10186-10199. [DOI: 10.1039/d2fo01682f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), an increasingly serious health issue in the world, was characterized as lipid metabolic disorder without a satisfactory treatment. Nobiletin (NOB), a citrus flavonoid, was considered...
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Lefebvre P, Staels B. Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease. Nat Rev Endocrinol 2021; 17:662-670. [PMID: 34417588 DOI: 10.1038/s41574-021-00538-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2021] [Indexed: 12/14/2022]
Abstract
The liver is often thought of as a single functional unit, but both its structural and functional architecture make it highly multivalent and adaptable. In any given physiological situation, the liver can maintain metabolic homeostasis, conduct appropriate inflammatory responses, carry out endobiotic and xenobiotic transformation and synthesis reactions, as well as store and release multiple bioactive molecules. Moreover, the liver is a very resilient organ. This resilience means that chronic liver diseases can go unnoticed for decades, yet culminate in life-threatening clinical complications once the adaptive capacity of the liver is overwhelmed. Non-alcoholic fatty liver disease (NAFLD) predisposes individuals to cirrhosis and increases liver-related and cardiovascular disease-related mortality. This Review discusses the accumulating evidence of sexual dimorphism in NAFLD, which is currently rarely considered in preclinical and clinical studies. Increased awareness of the mechanistic causes of hepatic sexual dimorphism could lead to improved understanding of the biological processes that are dysregulated in NAFLD, to the identification of relevant therapeutic targets and to improved risk stratification of patients with NAFLD undergoing therapeutic intervention.
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Affiliation(s)
- Philippe Lefebvre
- Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France.
| | - Bart Staels
- Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France
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24
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Hu Y, Du G, Li G, Peng X, Zhang Z, Zhai Y. The miR-122 inhibition alleviates lipid accumulation and inflammation in NAFLD cell model. Arch Physiol Biochem 2021; 127:385-389. [PMID: 31311339 DOI: 10.1080/13813455.2019.1640744] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/02/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Accumulating evidence showed that the expression of miR-122 was abnormal in NAFLD patients; however, the role of miR-122 on lipid accumulation and inflammation in NAFLD is not clear. METHODS RT-qPCR was applied to detect the expression levels of miR-122 and pro-inflammatory cytokines following transfected with miR-122 inhibitor or treated with oleic acid (OA). Detection of lipid accumulation was performed by triglyceride content test and oil red o staining assay. Western blotting was applied to detect the protein levels of TLR7, TLR4, MyD88 and NF-κBp65. RESULTS We found that the OA promoted lipid accumulation and pro-inflammatory cytokines secretion and activated TLR4/MyD88/NF-κBp65 signalling pathway, which were restored following transfected with miR-122 inhibitor. CONCLUSIONS These results suggested that miR-122 inhibition alleviates lipid accumulation and inflammation in L02 cell induced by OA may through inhibiting TLR4/MyD88/NF-κBp65 signalling pathway. The protective mechanism of miR-122 inhibition in NAFLD must be explored in future studies.
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Affiliation(s)
- Yiyi Hu
- Department of Gastroenterology, Shunde Hospital of Southern Medical University, Foshan, China
| | - Guoping Du
- Department of Gastroenterology, Shunde Hospital of Southern Medical University, Foshan, China
| | - Guohua Li
- Department of Gastroenterology, Shunde Hospital of Southern Medical University, Foshan, China
| | - Xuetao Peng
- Department of Gastroenterology, Shunde Hospital of Southern Medical University, Foshan, China
| | - Zhiqiao Zhang
- Department of Infectious Diseases, Shunde Hospital of Southern Medical University, Foshan, China
| | - Yingji Zhai
- Department of Gastroenterology, Shunde Hospital of Southern Medical University, Foshan, China
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25
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Quercetin Reduces Hepatic Fibrogenesis by Inhibiting TGF-β/Smad3 Signaling Pathway in LX-2 Cell Line. Jundishapur J Nat Pharm Prod 2021. [DOI: 10.5812/jjnpp.113484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Liver fibrosis has become one of the leading causes of morbidity and mortality in the world. Liver fibrosis progresses to cirrhosis and can eventually lead to hepatocellular carcinoma (HCC). During fibrogenesis, the hepatic stellate cells (HSCs) remain active and continuously produce more extracellular matrix (ECM). Quercetin, one of the main flavonoids in vegetables, has shown hepatoprotective potential, but its effects on liver fibrosis are not apparent. Objectives: In this study, we investigated the antifibrotic activity of quercetin following stimulation of TGF-β in the LX-2 cell line (a type of HSC-derived cell line) and its underlying mechanism in vitro. Methods: The LX-2 cells were treated with TGF-β1 (2 ng/mL) for 24 h. Next, the cells were treated with quercetin for 24 h, and the mRNA expression of α-smooth muscle actin (α-SMA), collagen1α1, and p-Smad3 protein levels were measured. Results: The results showed that the expression of α-SMA, collagen 1α1 (COL1α1) genes, and also the level of p-Smad3 protein in the presence of TGF-β increased significantly compared to the control group. Moreover, quercetin in concentrations of 75 and 100 μM inhibited TGF-β1-induced expression of α-SMA and COL1α1 genes and the p-Smad3 protein in LX-2 cells. Conclusions: We conclude that quercetin inhibits further activation of HSCs by inhibiting the TGF-β/Smad3 signaling pathway and reduces ECM accumulation during liver fibrosis in vitro, and may prevent the progression of liver fibrosis. Thus, the use of quercetin is suggested as a potential therapeutic agent in the treatment of liver fibrosis.
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Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview. Pharmacol Res 2021; 170:105739. [PMID: 34171492 DOI: 10.1016/j.phrs.2021.105739] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/07/2021] [Accepted: 06/19/2021] [Indexed: 02/08/2023]
Abstract
Fibrosis is characterized by an abnormal accumulation of extracellular matrix (ECM) constituents in the liver parenchyma that lead to hepatic cirrhosis. After liver injury, the hepatic stellate cells (HSCs) undergo a response called "activation", transforming the cells into proliferative, fibrogenic and contractile myofibroblasts, representing the main collagen-producing cells in the injured tissue. Activated HSCs are considered as pro-inflammatory cells producing cytokines and several hepatomatogens; they are additionally involved in the recruitment of Kupffer cells, circulating monocytes and macrophages through the production of chemokines. Moreover, HSC have been proposed as being involved in the development of insulin resistance mainly mediated by their inflammatory properties, which undeniably links their activation to the development of diabetes and Non-alcoholic fatty liver disease. In addition, when the liver is injured, a complex interaction between hepatocytes and HSCs occurs, inducing mitochondrial dysfunction, which contributes to the accumulation of fats in hepatocytes that trigger to liver lipotoxicity. These mechanisms underlying the activation of HSC suggest their major role in the development of metabolic disorders. It turns out that several molecules including MicroRNAs and proteins have the ability to inhibit the activation and the proliferation of HSCs, which makes them interesting therapeutic targets for the subsequent management of metabolic conditions. This review focuses on the mechanisms and molecular pathways underlying the initiation and onset of metabolic disorders following HSCs activation, as well as on molecular therapeutic targets, which could limit their fibrogenic transdifferentiation and therefore improve the liver condition in the course of metabolic imbalance.
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Affiliation(s)
- Nabila Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland.
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27
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Geier A, Tiniakos D, Denk H, Trauner M. From the origin of NASH to the future of metabolic fatty liver disease. Gut 2021; 70:gutjnl-2020-323202. [PMID: 33632710 PMCID: PMC8292567 DOI: 10.1136/gutjnl-2020-323202] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term 'fatty liver hepatitis' first appeared in 1962, it was in 1980 that the term 'non-alcoholic steatohepatitis' (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.
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Affiliation(s)
- Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Bayern, Germany
| | - Dina Tiniakos
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece & Translational & Clinical Research Institute; Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helmut Denk
- Institute of Pathology, Medical University of Graz, Graz, Steiermark, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Wien, Wien, Austria
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28
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Zeng F, Zhang Y, Han X, Zeng M, Gao Y, Weng J. Predicting Non-Alcoholic Fatty Liver Disease Progression and Immune Deregulations by Specific Gene Expression Patterns. Front Immunol 2021; 11:609900. [PMID: 33574818 PMCID: PMC7870871 DOI: 10.3389/fimmu.2020.609900] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide with rising rates in parallel to obesity, type 2 diabetes, and metabolic syndrome. NAFLD includes pathologies ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis and cirrhosis (NASH), which may eventually develop into hepatocellular carcinoma (HCC). Mechanically, lipids accumulation and insulin resistance act as the first hit, inflammation and fibrosis serve as the second hit. Currently, the diagnosis of NAFLD mainly depends on pathology examination and medical imaging, whereas proper gene signature classifiers are necessary for the evaluation of disease status. Here, we developed three signature classifiers to distinguish different NAFLD disease states (NAFL and NASH). Moreover, we found that B cells, DCs, and MAIT cells are key deregulated immune cells in NAFLD, which are associated with NAFLD and NAFLD-HCC progression. Meanwhile, AKR1B10 and SPP1 are closely related to the above three immune cell infiltrations and immunosuppressive cytokines expressions in NAFLD and NAFLD-HCC. Subsequently, we screened out AKR1B10 and SPP1 sensitive molecules TGX-221, which may provide a possible therapy for NAFLD and NAFLD-HCC.
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Affiliation(s)
- Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Min Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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Cai H, Bai Z, Ge RL. Hypoxia-inducible factor-2 promotes liver fibrosis in non-alcoholic steatohepatitis liver disease via the NF-κB signalling pathway. Biochem Biophys Res Commun 2021; 540:67-74. [PMID: 33450482 DOI: 10.1016/j.bbrc.2021.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 12/31/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases. Chronic hypoxia is related to the pathogenesis of NASH. HIF-2α is the key gene for lipid metabolism, fibrosis, and inflammation in many cells. To identify the molecular mechanism through which hypoxia exposure increases the morbidity of NASH, the expression level of HIF-2α was analysed and was found to be upregulated in human NASH liver. By constructing the NASH model of chronic hypoxia, the mice were housed at an altitude of 4300 m for 4 and 8 weeks, compared to the control groups that were housed at an altitude of 50 m. Histological studies showed that exposure to hypoxia promoted the activation of NF-κB by upregulating the expression of HIF-2α, as well as that of the genes related to inflammation and fibrosis, thereby promoting the development of NASH both in vivo and in vitro. In summary, hypoxia-exposure could upregulate HIF-2α to aggravate tissue fibrosis and inflammation by upregulating inflammation-related genes and fibrosis-related genes metabolites via the activated NF-κB pathway in NASH. Our results suggest that for NASH patients living at high altitudes, drug therapy could focus on treating tissue fibrosis and inflammation, and thus provides a new strategy for NASH treatment.
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Affiliation(s)
- Hao Cai
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China; Oncology Department, The Fifth People's Hospital of Qinghai Provincial, Xining, 810000, PR China
| | - Zhenzhong Bai
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China.
| | - Ri-Li Ge
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China.
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30
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Takamisawa K, Sugita N, Komatsu S, Wakasugi M, Yokoseki A, Yoshihara A, Kobayashi T, Nakamura K, Onodera O, Momotsu T, Endo N, Sato K, Narita I, Yoshie H, Tabeta K. Association between serum IgG antibody titers against Porphyromonas gingivalis and liver enzyme levels: A cross-sectional study in Sado Island. Heliyon 2020; 6:e05531. [PMID: 33294679 PMCID: PMC7683334 DOI: 10.1016/j.heliyon.2020.e05531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/28/2020] [Accepted: 11/12/2020] [Indexed: 12/11/2022] Open
Abstract
Background Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.
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Affiliation(s)
- Kei Takamisawa
- Division of Periodontology, Department of Oral Biological Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
| | - Noriko Sugita
- Division of Periodontology, Department of Oral Biological Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
| | - Shigeki Komatsu
- Sado General Hospital, 161 Chigusa, Sado City, Niigata, 952-1209, Japan
| | - Minako Wakasugi
- Department of Inter-Organ Communication Research, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan
| | - Akio Yokoseki
- Department of Inter-Organ Communication Research, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan
| | - Akihiro Yoshihara
- Division of Oral Science and Health Promotion, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
| | - Tetsuo Kobayashi
- Division of Periodontology, Department of Oral Biological Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan.,General Dentistry and Clinical Education Unit, Faculty of Dentistry & Medical and Dental Hospital, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
| | - Kazutoshi Nakamura
- Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan
| | - Takeshi Momotsu
- Sado General Hospital, 161 Chigusa, Sado City, Niigata, 952-1209, Japan
| | - Naoto Endo
- Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kenji Sato
- Sado General Hospital, 161 Chigusa, Sado City, Niigata, 952-1209, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Hiromasa Yoshie
- Division of Periodontology, Department of Oral Biological Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
| | - Koichi Tabeta
- Division of Periodontology, Department of Oral Biological Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakko-cho, Chuo-ku, Niigata, 951-8514, Japan
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Shao C, Ye J, Li F, Lin Y, Wu T, Wang W, Feng S, Zhong B. Early Predictors of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease: Non-obese Versus Obese Patients. Dig Dis Sci 2020; 65:1850-1860. [PMID: 31724099 DOI: 10.1007/s10620-019-05926-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 10/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is regarded as a risk factor of cardiovascular disease (CVD). However, the association between non-obese NAFLD and CVD has not been well established. AIM We aimed to compare the CVD risk between non-obese and obese NAFLD patients, and explored the factors associated with subclinical atherosclerosis. METHOD Consecutive NAFLD patients estimated by magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) were recruited. Liver fat content (LFC) and liver stiffness were measured with MRI-PDFF and shear wave elastography, respectively. CVD risk was estimated by atherosclerosis index (AI), carotid intima-media thickness, carotid plaque, and Framingham risk score (FRS). RESULTS This study included 543 NAFLD patients. The presence of carotid intima-media thickening and carotid plaque, FRS, and AI were comparable between non-obese and obese patients. Age increased per 10 years (OR 9.68; P < 0.001) and liver fibrosis (liver stiffness > 6.1 kPa, OR 4.42; P = 0.004) were significant factors associated with carotid intima-media thickening in non-obese patients, while age increased per 10 years (OR 2.02; P < 0.001), liver fibrosis (OR 2.18; P = 0.039), and LFC > 10% (OR 2.29; P = 0.021) were independent predictors in obese patients. Only elevated triglyceride was significantly associated with carotid plaque in non-obese patients (OR 2.42; P = 0.033), while age increased per 10 years (OR 1.77; P = 0.002) and LFC > 10% (OR 2.83; P = 0.019) were significant predictors in obese patients. CONCLUSIONS Liver stiffness and age were strongly predictive of subclinical atherosclerosis in all NAFLD, while LFC was an additional predictor in obese NAFLD patients. Our findings highlight that early CVD screening strategy should be established for NAFLD patients according to different BMIs.
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Affiliation(s)
- Congxiang Shao
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Junzhao Ye
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Fuxi Li
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Yansong Lin
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Tingfeng Wu
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Wei Wang
- Department of Medical Ultrasonics of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Shiting Feng
- Department of Radiology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Bihui Zhong
- Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, China.
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Wang C, Zhou Y, Huang W, Chen Z, Zhu H, Mao F, Lin Y, Zhang X, Shen S, Zhong Y, Huang X, Chen C, Sun Q. The impact of pre-existed and SERM-induced non-alcoholic fatty liver disease on breast cancer survival: a meta-analysis. J Cancer 2020; 11:4597-4604. [PMID: 32489477 PMCID: PMC7255364 DOI: 10.7150/jca.44872] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/07/2020] [Indexed: 01/07/2023] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is a common disorder and a frequent side effect of endocrine therapy (ET) for breast cancer treatment. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were performed based on whether NAFLD was induced by ET administration Results: Eight cohorts from six studies including 3684 breast cancer patients were enrolled. NAFLD was significantly associated with advanced age (p < 0.001), obesity (p < 0.001), lymph node metastases (p = 0.003) and hormone receptor positivity (p < 0.001). NAFLD had no significant impact on disease free survival (DFS) [hazard ratio (HR) 1.07, 95% confidence interval (CI) = 0.64-1.77, p = 0.81] and overall survival (OS) (HR 1.29, 95% CI = 0.68-2.44, p = 0.44). In subgroup analyses, ET-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-ET-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-3.41, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-ET-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis.
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Affiliation(s)
- Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yidong Zhou
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Wei Huang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ziyuan Chen
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Hanjiang Zhu
- Department of Dermatology, 90 Medical Center Way, Surge 110, University of California, San Francisco, CA 94143-0989, United States
| | - Feng Mao
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yan Lin
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Xiaohui Zhang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Songjie Shen
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ying Zhong
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Xin Huang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Chang Chen
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
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Parry SA, Hodson L. Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review. Adv Ther 2020; 37:1381-1406. [PMID: 32146704 PMCID: PMC7140753 DOI: 10.1007/s12325-020-01281-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation; therefore, effective treatment strategies are required. Here we review the available intervention studies that have investigated the effects of changes in lifestyle (diet and exercise/physical activity) on NAFLD in patients with both NAFLD and T2D. On the basis of the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in body weight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~ 7–10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.
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Affiliation(s)
- Siôn A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, Oxford, UK
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Banerjee A, Das D, Paul R, Roy S, Bhattacharjee A, Prasad SK, Banerjee O, Mukherjee S, Maji BK. Altered composition of high-lipid diet may generate reactive oxygen species by disturbing the balance of antioxidant and free radicals. J Basic Clin Physiol Pharmacol 2020; 31:/j/jbcpp.ahead-of-print/jbcpp-2019-0141/jbcpp-2019-0141.xml. [PMID: 32229664 DOI: 10.1515/jbcpp-2019-0141] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Background In the present era, obesity is increasing rapidly, and high dietary intake of lipid could be a noteworthy risk factor for the occasion of obesity, as well as nonalcoholic fatty liver disease, which is the independent risk factor for type 2 diabetes and cardiovascular disease. For a long time, high-lipid diet (HLD) in "fast food" is turning into part of our everyday life. So, we were interested in fulfilling the paucity of studies by means of preliminary evaluation of these three alternative doses of HLD on a rat model and elucidating the possible mechanism of these effects and divulging the most alarming dose. Methods Thirty-two rats were taken, and of these, 24 were fed with HLD in three distinctive compositions of edible coconut oil and vanaspati ghee in a ratio of 2:3, 3:2 and 1:1 (n = 8), orally through gavage at a dose of 10 mL/kg body weight for a period of 28 days, whereas the other eight were selected to comprise the control group. Results After completion of the experiment, followed by analysis of data it was revealed that hyperlipidemia with increased liver and cardiac marker enzymes, are associated with hepatocellular injury and cardiac damage. The data also supported increased proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). As oxidative stress parameter increased in both liver and heart, there is also an increased in TNF-α due to an increased expression of inducible nitric oxide (NO) synthase, which led to a high production of NO. Moreover, HLD treatment explicitly weakens reasonability of hepatocytes and cardiomyocytes conceivably through G0/G1 or S stage capture or perhaps by means of enlistment of sub-G0/G1 DNA fragmentation and a sign of apoptosis. Conclusions Based on the outcomes, it tends to be inferred that consequences of the present examination uncovered HLD in combination of 2:3 applies most encouraging systemic damage by reactive oxygen species generation and hyperlipidemia and necroapoptosis of the liver and heart. Hence, outcome of this study may help to formulate health care strategy and warns about the food habit in universal population regarding the use of hydrogenated and saturated fats (vanaspati ghee) in diet.
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Affiliation(s)
- Arnab Banerjee
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Debasmita Das
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Rajarshi Paul
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Sandipan Roy
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Ankita Bhattacharjee
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Shilpi Kumari Prasad
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Oly Banerjee
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Sandip Mukherjee
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India
| | - Bithin Kumar Maji
- Department of Physiology (UG and PG), Serampore College, 9 William Carey Road, Serampore, Hooghly-712201, West Bengal, India, Phone: +91-9433509890
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Roeb E. Das klinische Bild der nichtalkoholischen Fettlebererkrankung. DER GASTROENTEROLOGE 2020; 15:78-87. [DOI: 10.1007/s11377-020-00425-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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36
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Griffin DM, Bitner BR, Criss Ii Z, Marcano D, Berlin JM, Kent TA, Tour JM, Samson SL, Pautler RG. Use of a bioengineered antioxidant in mouse models of metabolic syndrome. Expert Opin Investig Drugs 2020; 29:209-219. [PMID: 31937152 DOI: 10.1080/13543784.2020.1716216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Background: Oxidative stress has been implicated in metabolic syndrome (MetS); however, antioxidants such as vitamin E have had limited success in the clinic. This prompts the question of what effects amore potent antioxidant might produce. A prime candidate is the recently developed bioengineered antioxidant, poly(ethylene glycol)-functionalizedhydrophilic carbon clusters (PEG-HCCs), which are capable of neutralizing the reactive oxygen species (ROS) superoxide anion and hydroxyl radical at106/molecule of PEG-HCC. In this project, we tested the potential of PEG-HCCs as a possible therapeutic for MetS.Results: PEG-HCC treatment lessened lipid peroxidation, aspartate aminotransferase levels, non-fastingblood glucose levels, and JNK phosphorylation inob/ob mice. PEG-HCC-treated WT mice had an increased response to insulin by insulin tolerance tests and adecrease in blood glucose by glucose tolerance tests. These effects were not observed in HFD-fed mice, regardless of treatment. PEG-HCCs were observed in the interstitial space of liver, spleen, skeletal muscle, and adipose tissue. No significant difference was shown in gluconeogenesis or inflammatory gene expression between treatment and dietary groups.Expert Opinion: PEG-HCCs improved some parameters of disease possibly due to a resulting increase in peripheral insulin sensitivity. However, additional studies are needed to elucidate how PEG-HCCsare producing these effects.
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Affiliation(s)
- Deric M Griffin
- Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Brittany R Bitner
- Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Zachary Criss Ii
- Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Daniela Marcano
- Department of Chemistry, Rice University, Houston, TX, USA.,Smalley-Curl Institute for and Nanocarbon Center, Rice University, Houston, TX, USA
| | - Jacob M Berlin
- Department of Chemistry, Rice University, Houston, TX, USA.,Smalley-Curl Institute for and Nanocarbon Center, Rice University, Houston, TX, USA.,Molecular Medicine, City of Hope, Duarte, CA, USA
| | - Thomas A Kent
- Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.,Department of Neurology, Baylor College of Medicine, Houston, TX, USA.,Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX, USA
| | - James M Tour
- Department of Chemistry, Rice University, Houston, TX, USA.,Smalley-Curl Institute for and Nanocarbon Center, Rice University, Houston, TX, USA
| | - Susan L Samson
- Department of Chemistry, Rice University, Houston, TX, USA.,Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Robia G Pautler
- Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
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Kempinska-Podhorodecka A, Wunsch E, Milkiewicz P, Stachowska E, Milkiewicz M. The Association between SOCS1-1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients. J Clin Med 2019; 8:jcm8111912. [PMID: 31717271 PMCID: PMC6912432 DOI: 10.3390/jcm8111912] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/31/2019] [Accepted: 11/06/2019] [Indexed: 12/20/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS) proteins prevent uncontrolled cytokine signaling and appear to play a role in the pathological processes behind obesity and insulin resistance. The polymorphism of the SOCS1 gene (rs243330, −1656G>A) is associated with obesity and glucose sensitivity. To estimate the effect of this SOCS1 gene polymorphism on nonalcoholic fatty liver disease (NAFLD) susceptibility, we performed a study on 138 patients with ultrasound-confirmed NAFLD and 1000 healthy blood donors. The relationship between the SOCS1−1656G>A polymorphism and serum biochemical parameters in NAFLD was additionally investigated. The SOCS1 variant was genotyped using a dedicated TaqMan assay. The frequency of rs243330 polymorphism did not differ between patients and controls. However, in a cohort of obese individuals (BMI ≥ 30 kg/m2) the occurrence of the G allele of the SOCS1−1656G>A polymorphism was strongly associated with NAFLD (odds ratio (OR) 1.6; 95% CI,1.1–2.5; p = 0.009), and carriers of the AA genotype have lower risk of developing NAFLD (OR 0.4; 95% CI, 0.2–0.7; p = 0.004). Overweight NAFLD patients who were carriers of GG genotypes had significantly lower levels of homeostasis model assessment of insulin resistance (HOMA-IR) values (p = 0.03 vs. AA), and the obese GG homozygotes had lower serum concertation of triglyceride (GG vs. AA; p = 0.02). Serum liver enzyme activities were not modified by the presence of SOCS1 risk variants. In conclusion, the observed phenotype of overweight NAFLD patients with non-elevated levels of TG and HOMA-IR, which is associated with genetic variants of SOCS1, provides a rationale for further research on the pathophysiology of fatty liver disease.
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Affiliation(s)
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University, 71-210 Szczecin, Poland; (E.W.); (P.M.)
| | - Piotr Milkiewicz
- Translational Medicine Group, Pomeranian Medical University, 71-210 Szczecin, Poland; (E.W.); (P.M.)
- Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, 71-460 Szczecin, Poland;
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland;
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Antioxidant Versus Pro-Apoptotic Effects of Mushroom-Enriched Diets on Mitochondria in Liver Disease. Int J Mol Sci 2019; 20:ijms20163987. [PMID: 31426291 PMCID: PMC6720908 DOI: 10.3390/ijms20163987] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/14/2019] [Accepted: 08/14/2019] [Indexed: 12/13/2022] Open
Abstract
Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis that results in an increased hepatic fatty acid influx and the ectopic accumulation of fat in the liver. Upregulation of beta-oxidation as one compensatory mechanism leads to an increase in mitochondrial tricarboxylic acid cycle flux and ATP generation. The progression of NAFLD is associated with alterations in the mitochondrial molecular composition and respiratory capacity, which increases their vulnerability to different stressors, including calcium and pro-inflammatory molecules, which result in an increased generation of reactive oxygen species (ROS) that, altogether, may ultimately lead to mitochondrial dysfunction. This may activate further pro-inflammatory pathways involved in the progression from steatosis to steatohepatitis (NASH). Mushroom-enriched diets, or the administration of their isolated bioactive compounds, have been shown to display beneficial effects on insulin resistance, hepatic steatosis, oxidative stress, and inflammation by regulating nutrient uptake and lipid metabolism as well as modulating the antioxidant activity of the cell. In addition, the gut microbiota has also been described to be modulated by mushroom bioactive molecules, with implications in reducing liver inflammation during NAFLD progression. Dietary mushroom extracts have been reported to have anti-tumorigenic properties and to induce cell-death via the mitochondrial apoptosis pathway. This calls for particular attention to the potential therapeutic properties of these natural compounds which may push the development of novel pharmacological options to treat NASH and HCC. We here review the diverse effects of mushroom-enriched diets in liver disease, emphasizing those effects that are dependent on mitochondria.
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Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells 2019; 8:cells8080845. [PMID: 31394730 PMCID: PMC6721710 DOI: 10.3390/cells8080845] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis.
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40
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Cao B, Sun RB, Yan G, Yang GY, Aa JY, Li J. Berberine reverses LPS-induced repression of CYP7A1 through an anti-inflammatory effect. CHINESE HERBAL MEDICINES 2019. [DOI: 10.1016/j.chmed.2019.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Sundelin EIO, Gormsen LC, Heebøll S, Vendelbo MH, Jakobsen S, Munk OL, Feddersen S, Brøsen K, Hamilton-Dutoit SJ, Pedersen SB, Grønbaek H, Jessen N. Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease. Br J Clin Pharmacol 2019; 85:1761-1770. [PMID: 30973968 DOI: 10.1111/bcp.13962] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 04/05/2019] [Accepted: 04/06/2019] [Indexed: 12/14/2022] Open
Abstract
AIMS Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome, but whether NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. METHODS Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). RESULTS We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (NASH) (Vd 2.38 ± 0.56 vs. 2.10 ± 0.39, P = 0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription. CONCLUSION Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings imply that metformin action in liver in patients with NAFLD may be preserved.
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Affiliation(s)
| | | | - Sara Heebøll
- Department of Gastroenterology & Hepatology, Aarhus University Hospital, Denmark
| | - Mikkel Holm Vendelbo
- Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Denmark.,Department of Biomedicine, Aarhus University, Denmark
| | - Steen Jakobsen
- Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Denmark
| | - Ole Lajord Munk
- Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Denmark
| | - Søren Feddersen
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Kim Brøsen
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.,Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Denmark
| | | | - Steen Bønløkke Pedersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark.,Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark
| | - Henning Grønbaek
- Department of Gastroenterology & Hepatology, Aarhus University Hospital, Denmark
| | - Niels Jessen
- Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Denmark.,Department of Biomedicine, Aarhus University, Denmark.,Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark.,Department of Clinical Pharmacology, Aarhus University Hospital, Denmark
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Kennedy L, Francis H, Alpini G. Hepatocyte-specific and extra-hepatocyte actions of perilipin-2 during fatty liver disease: benefits of being extra. J Physiol 2019; 597:1431-1432. [PMID: 30656685 DOI: 10.1113/jp277539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Lindsey Kennedy
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Heather Francis
- Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.,Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gianfranco Alpini
- Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.,Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Zhang L, Yao Z, Ji G. Herbal Extracts and Natural Products in Alleviating Non-alcoholic Fatty Liver Disease via Activating Autophagy. Front Pharmacol 2018; 9:1459. [PMID: 30618753 PMCID: PMC6297257 DOI: 10.3389/fphar.2018.01459] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease world-wide, and currently therapeutic options for NAFLD are limited. Herbal medicine (HM) may offer an attractive alternative for the treatment of NAFLD. Recent years have witnessed a growing interest in the autophagy-inducing agents, and autophagy activation has been recognized as an efficient strategy in managing NAFLD and related complications. Pharmacological studies have demonstrated certain potential of HM extracts and natural products in inducing autophagy, which might contribute to the efficacy of HM in preventing and treating NAFLD. This review aims to summarize current understanding of mechanisms of HM extracts and natural products in preventing and treating NAFLD. Specially, we focused on mechanisms by which autophagy can target the main pathogenesis events associated with NAFLD, including hepatic steatosis, inflammation, oxidative stress, and apoptosis. It is hoped that this brief review can provide a general understanding of HM extracts and natural products in treating NAFLD, and raise awareness of potential clinical application of HM in general.
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Affiliation(s)
- Li Zhang
- Institute of Digestive Diseases, China-Canada Center of Research for Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zemin Yao
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Guang Ji
- Institute of Digestive Diseases, China-Canada Center of Research for Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Chen K, Ma J, Jia X, Ai W, Ma Z, Pan Q. Advancing the understanding of NAFLD to hepatocellular carcinoma development: From experimental models to humans. Biochim Biophys Acta Rev Cancer 2018; 1871:117-125. [PMID: 30528647 DOI: 10.1016/j.bbcan.2018.11.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/28/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has recently been recognized as an important etiology contributing to the increased incidence of hepatocellular carcinoma (HCC). NAFLD, characterized by fat accumulation in the liver, is affecting at least one-third of the global population. The more aggressive form, nonalcoholic steatohepatitis (NASH), is characterized by hepatocyte necrosis and inflammation. The development of effective approaches for disease prevention and/or treatment heavily relies on deep understanding of the mechanisms underlying NAFLD to HCC development. However, this has been largely hampered by the lack of robust experimental models that recapitulate the full disease spectrum. This review will comprehensively describe the current in vitro and mouse models for studying NAFLD/NASH/HCC, and further emphasize their applications and possible future improvement for better understanding the molecular mechanisms involved in the cascade of NAFLD to HCC progression.
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Affiliation(s)
- Kan Chen
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China; Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Jianbo Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Xiaoyuan Jia
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Wen Ai
- Department of Cardiology, Shenzhen Nanshan People's Hospital, China
| | - Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Qiuwei Pan
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China; Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
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Prevalence of Nephrolithiasis in Patients with Chronic Liver Disease: A Case-Control Study. J Clin Exp Hepatol 2018; 8:375-379. [PMID: 30563998 PMCID: PMC6286439 DOI: 10.1016/j.jceh.2018.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Nephrolithiasis is known to be associated with several systemic diseases including chronic kidney disease and renal failure, which can also occur as a complication of chronic liver disease (CLD). This study aimed to assess the prevalence of nephrolithiasis in patients with CLD. METHODS A short survey was completed by 198 patients with CLD and 322 controls matched by age, sex, and state of residence. A primary diagnosis of liver disease was confirmed with health record review. RESULTS The median age of the liver disease group was 63 years and 128 (65%) were male; the median age of the control group was 63 and 199 (63%) were male. Body mass index was higher in the liver disease group (27.8 vs 26.7, P < .01). The most common liver disease diagnosis was hepatitis C (60 [30%]) followed by alcoholic cirrhosis (42 [21.2%]). The self-reported prevalence of nephrolithiasis in the liver disease group was 26%, compared to 14% in the control group (P < .01). This association remained significant after adjusting for age, sex, body mass index, and family history of kidney stones or liver disease. CONCLUSIONS In this case-control, survey-based study, the prevalence of nephrolithiasis was 2 times higher in patients with CLD.
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Santoleri D, Titchenell PM. Resolving the Paradox of Hepatic Insulin Resistance. Cell Mol Gastroenterol Hepatol 2018; 7:447-456. [PMID: 30739869 PMCID: PMC6369222 DOI: 10.1016/j.jcmgh.2018.10.016] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/30/2018] [Accepted: 10/30/2018] [Indexed: 12/12/2022]
Abstract
Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin's control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway.
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Affiliation(s)
- Dominic Santoleri
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Paul M. Titchenell
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,Correspondence Address correspondence to: Paul M. Titchenell, PhD, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. fax: (215) 898-5408.
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Dou X, Li S, Hu L, Ding L, Ma Y, Ma W, Chai H, Song Z. Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease. Exp Mol Med 2018; 50:1-16. [PMID: 29622764 PMCID: PMC5938004 DOI: 10.1038/s12276-017-0013-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 11/01/2017] [Indexed: 12/30/2022] Open
Abstract
Oxidative stress and TNFα are critically involved in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of dysregulated glutathione homeostasis, a principal feature of oxidative stress, on TNFα-induced hepatotoxicity and its mechanistic implications in NAFLD progression. We showed that mice fed a high-fat diet (HFD) for 12 weeks developed hepatic steatosis and liver injuries, which were associated with not only TNFα overproduction but also hepatic glutathione dysregulation, characterized by GSH reduction and GSSG elevation. Moreover, consuming a HFD increased protein S-glutathionylation (protein-SSG formation) in the liver. Subsequent cell culture studies revealed that GSSG accumulation, as opposed to GSH reduction, sensitized hepatocytes to TNFα killing by reducing the TNFα-triggered NF-κB activity. GSSG prevented TNFα-induced activation of IKK-β, an upstream kinase in the NF-κB signaling pathway, by inducing IKK-β glutathionylation (IKK-β-SSG formation). In animal studies, in comparison to a control diet, HFD consumption resulted in increased hepatic IKK-β-SSG formation, leading to suppressed IKK-β activation and subsequent NF-κB suppression. Furthermore, we found that HFD consumption also led to decreased hepatic expression of glutaredoxin, a key enzyme for de-glutathionylation. Similarly, CdCl2, a chemical inhibitor of glutaredoxin, sensitized hepatocytes to TNFα-mediated cytotoxicity. In conclusion, our data suggest that GSSG is a potent and clinically relevant sensitizer for TNFα-induced hepatotoxicity in NAFLD, which represents a potential therapeutic target for NAFLD.
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Affiliation(s)
- Xiaobing Dou
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, 60612, USA
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Songtao Li
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, 60612, USA
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086, P. R. China
| | - Linfeng Hu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Lei Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Yue Ma
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Wang Ma
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Hui Chai
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, 60612, USA.
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P. R. China.
- Department of Pathology, University of Illinois Medical Center, Chicago, IL, 60612, USA.
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Lodhi M, Amin J, Eswaran S. Role of alcohol in nonalcoholic steatohepatitis: Rush university (Con) patients with nonalcoholic steatohepatitis should be abstinent from alcohol use. Clin Liver Dis (Hoboken) 2018; 11:39-42. [PMID: 30992785 PMCID: PMC6314280 DOI: 10.1002/cld.669] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 09/07/2017] [Accepted: 09/12/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- Maham Lodhi
- Department of MedicineRush University Medical CenterChicagoIL
| | - Jaimin Amin
- Department of MedicineRush University Medical CenterChicagoIL
| | - Sheila Eswaran
- Department of MedicineRush University Medical CenterChicagoIL
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Devisscher L, Scott CL, Lefere S, Raevens S, Bogaerts E, Paridaens A, Verhelst X, Geerts A, Guilliams M, Van Vlierberghe H. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. Cell Immunol 2017; 322:74-83. [PMID: 29111158 DOI: 10.1016/j.cellimm.2017.10.006] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/13/2017] [Accepted: 10/14/2017] [Indexed: 12/31/2022]
Abstract
Kupffer cells (KCs) and monocyte-derived macrophages are implicated in non-alcoholic steatohepatitis (NASH) pathogenesis but their functions remain unclear due to the lack of specific markers to distinguish between the different cell types. Additionally, it is unclear if multiple subsets of KCs are present during NASH. Here, we characterized the liver macrophage subsets during methionine/choline deficient (MCD) diet-induced NASH and recovery. We observed a significant reduced contribution of Ly6CloClec4F+Tim4+KCs to the hepatic macrophage pool in MCD fed mice, which normalized during recovery. Ly6CloClec4F-Tim4- monocyte-derived macrophages increased during MCD feeding and returned to baseline during recovery. Ly6CloClec4F+Tim4- monocyte-derived KCs developed during initial recovery but did not self-renew as their numbers were reduced after full recovery. Initial recovery from MCD diet feeding was further characterized by increased proportions of Ki-67+ proliferating KCs. In conclusion, the hepatic macrophage pool undergoes substantial albeit transient changes during NASH and recovery, with the KC pool being maintained by proliferation and differentiation of short-lived monocyte-derived KCs.
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Affiliation(s)
- Lindsey Devisscher
- Department of Gastroenterology and Hepatology, Ghent University, Belgium.
| | - Charlotte L Scott
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, UK.
| | - Sander Lefere
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Eliene Bogaerts
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Annelies Paridaens
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University, Belgium
| | - Martin Guilliams
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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Bellentani S, Tiribelli C. Is it time to change NAFLD and NASH nomenclature? Lancet Gastroenterol Hepatol 2017; 2:547-548. [DOI: 10.1016/s2468-1253(17)30146-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/02/2017] [Indexed: 01/08/2023]
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