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1
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Kim YJ, Lee JR, Kim MR, Jeong JA, Kim JJ, Jeong KW. Protein kinase-mediated inhibition of autophagy by palmitic acid in hepatocytes. Eur J Pharmacol 2025; 998:177528. [PMID: 40113068 DOI: 10.1016/j.ejphar.2025.177528] [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: 01/24/2025] [Revised: 03/03/2025] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.
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Affiliation(s)
- Yeon Jeong Kim
- College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea
| | - Jae Rim Lee
- College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea
| | - Myeong Ryeo Kim
- College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea
| | - Jin Ah Jeong
- College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea
| | - Jung Ju Kim
- Autophagy Sciences Inc., Seoul, 08376, Republic of Korea
| | - Kwang Won Jeong
- College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea.
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Zhang Y, Ding R, Hu L, Liu E, Qu P. Epigenetics in metabolic dysfunction-associated steatohepatitis. Cell Signal 2025; 130:111684. [PMID: 39999913 DOI: 10.1016/j.cellsig.2025.111684] [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: 01/09/2025] [Revised: 02/16/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease involving genetics, environment, and lifestyle, with the potential to progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Although the pathogenesis of MASH is not fully clear, increasing evidence has indicated that epigenetics plays an important role in the genesis and progression of MASH, during which, as drastic changes in metabolites, epigenetics undergo drastic changes. Roles of chromatin structure, chromatin accessibility, DNA methylation, histone modification, and non-coding RNAs were considered as bridges of pathogenic factors and MASH. In this review, the research progress on the epigenetics of MASH was summarized, and indepth research and therapeutic strategies based on epigenetics is expected to bring new hope to MASH patients.
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Affiliation(s)
- Yanru Zhang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Ruike Ding
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
| | - Pengxiang Qu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
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3
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Moayedfard Z, Bagheri Lankarani K, Alizadeh AA, Nekooeian AA, Dara M, Koohpeyma F, Parsa S, Nikeghbalian S, Hosseinpouri A, Azarpira N. The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:334-350. [PMID: 40438157 PMCID: PMC12116527 DOI: 10.30476/ijms.2024.103376.3660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/01/2024] [Accepted: 09/22/2024] [Indexed: 06/01/2025]
Abstract
Background Due to the scarcity of treatment options, managing the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to cirrhosis necessitates innovative approaches. This study focused on endoplasmic reticulum (ER) stress, apoptosis, and autophagy as key mechanisms in NAFLD pathogenesis. It also highlighted the potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes as promising therapeutic options. Methods The study was conducted at the Department of Regenerative Medicine, Shiraz University of Medical Sciences, (Shiraz, Iran) from November 2021 to December 2023. The mice (n=32) were divided into four groups: control, high-fat diet (HFD) without treatment, HFD with AD-MSCs treatment, and HFD with AD-MSCs-derived exosomes groups. The mice were fed HFD for 8 weeks. They received MSC and exosomes for the last 3 weeks. One week after the final injection, mice were tested for serum testing, stereological analysis, and real-time polymerase chain reaction (RT-PCR). The data were analyzed using the Graph-Pad Prism software by one-way analysis of variance (ANOVA) with Tukey analysis as a post hoc comparison between groups. P<0.05 indicated a significant difference. Results AD-MSCs-exosomes significantly reduced ER stress indicators (IRE1α [P=0.0001], PERK [P=0.0006], ATF6 [P=0.0001], and GRP78 [P=0.0001]), apoptosis markers (Bax [P=0.005] and Cas3 [P=0.001]), and autophagic flux markers (P62 [P=0.0001] and LC3B/A [P=0.003]). Conclusion In this investigation, AD-MSCs-exosomes significantly restored autophagy and suppressed unfolded protein response (UPR) pathways in the early stages of NAFLD.
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Affiliation(s)
- Zahra Moayedfard
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ali Akbar Alizadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Akbar Nekooeian
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farhad Koohpeyma
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Endocrine and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shima Parsa
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Abu Ali Sina Hospital for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arghavan Hosseinpouri
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Jian Y, Li Y, Zhou Y, Mu W. Pollutants in Microenvironmental Cellular Interactions During Liver Inflammation Cancer Transition and the Application of Multi-Omics Analysis. TOXICS 2025; 13:163. [PMID: 40137490 PMCID: PMC11945810 DOI: 10.3390/toxics13030163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/18/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
This study categorizes pollutant-induced inflammation-cancer transition into three stages: non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and hepatocellular carcinoma (HCC). It systematically reveals the temporal heterogeneity of pollutant-induced liver damage. The findings indicate that pollutants not only directly damage hepatocytes but also modulate key cells in the immune microenvironment, such as hepatic stellate cells (HSCs) and Kupffer cells, thereby amplifying inflammatory and fibrotic responses, ultimately accelerating the progression of HCC. Mechanistically, in the early stage (NAFLD), pollutants primarily cause hepatocyte injury through oxidative stress and lipid metabolism dysregulation. During the fibrosis stage, pollutants promote liver fibrosis by inducing extracellular matrix accumulation, while in the HCC stage, they drive tumorigenesis via activation of the Wnt/β-catenin pathway and p53 inactivation. Through multi-omics analyses, this study identifies critical pathogenic molecules and signaling pathways regulated by pollutants, providing new insights into their pathogenic mechanisms, potential biomarkers, and therapeutic targets. These findings offer valuable guidance for the development of diagnostic and therapeutic strategies for liver diseases and the formulation of environmental health risk prevention measures.
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Affiliation(s)
| | | | | | - Wei Mu
- School of Public Health, Center for Single-Cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Y.J.); (Y.L.); (Y.Z.)
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5
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He X, Zhang S, Bai Q, Pan M, Jiang Y, Liu W, Li W, Gong Y, Li X. Air pollution exposure and prevalence of non-alcoholic fatty liver disease and related cirrhosis: A systematic review and meta-analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117469. [PMID: 39657383 DOI: 10.1016/j.ecoenv.2024.117469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND AND OBJECTIVE A systematic review and meta-analysis were used to investigate the relationship between air pollution exposure and the prevalence of non-alcoholic fatty liver disease (NAFLD) and its related cirrhosis. Through this study, we hope to clarify the potential public health risks of air pollution as an environmental exposure factor. METHODS Through a comprehensive and systematic search of the EMBASE, PubMed, Web of Science, and Cochrane library databases, studies published up to March 30, 2024, that met the eligibility criteria were identified. The meta-analysis aimed to determine the association between air pollution exposure and NAFLD risk. Subgroup analyses were conducted based on regional economic development after adjusting for confounding factors. The combined odds ratio (OR) was calculated, publication bias was assessed using funnel plots, and consideration was given to heterogeneity among study-specific relative risks. RESULTS This review included 14 observational studies (including 7 cohort studies and 7 cross-sectional studies) involving 43,475,41 participants. The pooled analysis showed that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels were positively associated with the incidence and prevalence of NAFLD and its related cirrhosis. The risk ratios for PM2.5, NOx, PM10, PM2.5-10, passive smoking, and air pollution from solid fuels for NAFLD and its related cirrhosis were 1.33 (95 % CI: 1.25, 1.42), 1.19 (95 % CI: 1.14, 1.23), 1.27 (95 % CI: 1.05, 1.55), 1.05 (95 % CI: 1.00, 1.11), 1.53 (95 % CI: 1.12, 2.09), 1.50 (95 % CI: 0.86, 2.63), and 1.18 (95 % CI: 0.85, 1.63), respectively. In contrast, the risk ratio for O3 was 0.75 (95 % CI: 0.69, 0.83), suggesting that O3 may lower the incidence and prevalence of NAFLD and its related cirrhosis. We also conducted subgroup analyses based on the level of national development to examine the impact of PM2.5 on NAFLD and its related cirrhosis. The results showed that the risk of NAFLD and its related cirrhosis associated with PM2.5 in developing countries was 1.41 (95 % CI: 1.29, 1.53), which was higher than 1.20 (95 % CI: 1.12, 1.29) in developed countries. CONCLUSION The study findings show that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels can increase an individual's risk of developing NAFLD and its related cirrhosis; while O3 can reduce the risk. In developing countries, the risk level of NAFLD and its related cirrhosis due to PM2.5 is higher than that in developed countries.
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Affiliation(s)
- Xingyi He
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Shipeng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Qinglin Bai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Moshen Pan
- School of Economics, Shanghai University of Finance and Economics, Shanghai 200433, PR China
| | - Yanjie Jiang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, No.157 Daming Road, Nanjing 210022, PR China
| | - Weiwei Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Wei Li
- Department of Intensive Care Medicine, Sichuan Hospital of Integrated Traditional Chinese and Western Medicine, Chengdu 610041, PR China
| | - Yuanyuan Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Xueping Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
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Gong X, Guo C, Liu J, Li Z, Ruan J, Tang M, Gu J, Shi H. Unraveling cadmium-driven liver inflammation with a focus on arachidonic acid metabolites and TLR4/ IκBα /NF-κB pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 286:117177. [PMID: 39418721 DOI: 10.1016/j.ecoenv.2024.117177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
Epidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.
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Affiliation(s)
- Xun Gong
- Department of Rheumatology & Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, China.
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Junlin Liu
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Zehua Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Jiacheng Ruan
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China.
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China.
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Eiser AR. Environmental, Metabolic, and Nutritional Factors Concerning Dementia in African American and Hispanic American Populations. Am J Med 2024; 137:939-942. [PMID: 38942346 PMCID: PMC11438570 DOI: 10.1016/j.amjmed.2024.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 06/17/2024] [Accepted: 06/17/2024] [Indexed: 06/30/2024]
Abstract
African Americans and Hispanic Americans experience a higher incidence and prevalence of dementia than white Americans while also experiencing more environmental, metabolic, and nutritional factors potentially promoting such disparities. Greater exposure to air, water, and soil pollutants, including toxic metals associated with neurodegeneration, accrues in both minorities, as does worse dental care than Whites exposing them to periodontitis, raising dementia risk. Hispanic Americans experience greater occupational exposure to herbicides and pesticides, and have a higher rate of developing non-alcoholic fatty liver disease (NAFLD), predisposing to dementia. African Americans have a greater likelihood of both vitamin D deficiency and magnesium deficiency, increasing neuroinflammation and dementia risk. Both have greater air pollution exposure, a known dementia risk. Nutritional changes, including greater nut consumption and reduced sugar drink consumption, improved dental care, and reduced toxicant exposure, may help reduce this higher risk of dementia among African Americans and Hispanic Americans.
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Affiliation(s)
- Arnold R Eiser
- Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
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He J, Qian YC, Yin YC, Kang JR, Pan TR. Polydatin: a potential NAFLD therapeutic drug that regulates mitochondrial autophagy through SIRT3-FOXO3-BNIP3 and PINK1-PRKN mechanisms - a network pharmacology and experimental investigation. Chem Biol Interact 2024; 398:111110. [PMID: 38876248 DOI: 10.1016/j.cbi.2024.111110] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/26/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder that is linked to metabolic syndrome, mitochondrial dysfunction and impaired autophagy. Polydatin (PD), a natural polyphenol from Polygonum cuspidatum, exhibits various pharmacological effects and protects against NAFLD. The aim of this study was to reveal the molecular mechanisms and therapeutic potential of PD for NAFLD, with a focus on the role of mitochondrial autophagy mediated by sirtuin 3 (SIRT3), fork-head box O3 (FOXO3) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), and by PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN). We combined network pharmacology analysis, animal models and cell culture experiments to show that PD could regulate the mitochondrial autophagy pathway by modulating several key genes related to mitochondrial function, and ameliorate the liver function, histopathology and mitochondrial biogenesis of NAFLD mice and hepatocytes by activating the SIRT3-FOXO3-BNIP3 axis and the PINK1-PRKN-dependent mechanism of mitochondrial autophagy. We also identified the core targets of PD, including SIRT3, FOXO3A, CASP3, PARKIN, EGFR, STAT3, MMP9 and PINK, and confirmed that silencing SIRT3 could significantly attenuate the beneficial effect of PD. This study provided novel theoretical and experimental support for PD as a promising candidate for NAFLD treatment, and also suggested new avenues and methods for investigating the role of mitochondrial autophagy in the pathogenesis and intervention of NAFLD.
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Affiliation(s)
- Jing He
- Department of Endocrinology, Anhui Medical University Hefei Third Clinical College, The Third People's Hospital of Hefei, Hefei, Anhui, China
| | | | - Ying-Chuan Yin
- Department of Endocrinology, Anhui Medical University Hefei Third Clinical College, The Third People's Hospital of Hefei, Hefei, Anhui, China
| | - Jing-Rui Kang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, China
| | - Tian-Rong Pan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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Ge WD, Du TT, Wang CY, Sun LN, Wang YQ. Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases. Biochem Pharmacol 2024; 225:116278. [PMID: 38740223 DOI: 10.1016/j.bcp.2024.116278] [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: 01/12/2024] [Revised: 04/25/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.
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Affiliation(s)
- Wen-Di Ge
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Tian-Tian Du
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Cao-Yang Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Lu-Ning Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China.
| | - Yong-Qing Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China.
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10
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Zhu X, Zeng C, Yu B. White adipose tissue in metabolic associated fatty liver disease. Clin Res Hepatol Gastroenterol 2024; 48:102336. [PMID: 38604293 DOI: 10.1016/j.clinre.2024.102336] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/28/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Metabolic associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, currently lacking universally recognized therapeutic drugs, thereby increasing the risk of cirrhosis and hepatocellular carcinoma. Research has reported an association between white adipose tissue and MAFLD. SCOPE OF REVIEW White adipose tissue (WAT) is involved in lipid metabolism and can contribute to the progression of MAFLD by mediating insulin resistance, inflammation, exosomes, autophagy, and other processes. This review aims to elucidate the mechanisms through which WAT plays a role in the development of MAFLD. MAJOR CONCLUSIONS WAT participates in the occurrence and progression of MAFLD by mediating insulin resistance, inflammation, autophagy, and exosome secretion. Fibrosis and restricted expansion of adipose tissue can lead to the release of more free fatty acids (FFA), exacerbating the progression of MAFLD. WAT-secreted TNF-α and IL-1β, through the promotion of JNK/JKK/p38MAPK expression, interfere with insulin receptor serine and tyrosine phosphorylation, worsening insulin resistance. Adiponectin, by inhibiting the TLR-4-NF-κB pathway and suppressing M2 to M1 transformation, further inhibits the secretion of IL-6, IL-1β, and TNF-α, improving insulin resistance in MAFLD patients. Various gene expressions within WAT, such as MBPAT7, Nrf2, and Ube4A, can ameliorate insulin resistance in MAFLD patients. Autophagy-related gene Atg7 promotes the expression of fibrosis-related genes, worsening MAFLD. Non-pharmacological treatments, including diabetes-related medications and exercise, can improve MAFLD.
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Affiliation(s)
- Xiaoqin Zhu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Chuanfei Zeng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Baoping Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China.
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Dashti Z, Yousefi Z, Kiani P, Taghizadeh M, Maleki MH, Borji M, Vakili O, Shafiee SM. Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth. Metabolism 2024; 154:155811. [PMID: 38309690 DOI: 10.1016/j.metabol.2024.155811] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/23/2024] [Accepted: 01/28/2024] [Indexed: 02/05/2024]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise, mirroring a global surge in diabetes and metabolic syndrome, as its major leading causes. NAFLD represents a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Mechanistically, we know the unfolded protein response (UPR) as a protective cellular mechanism, being triggered under circumstances of endoplasmic reticulum (ER) stress. The hepatic UPR is turned on in a broad spectrum of liver diseases, including NAFLD. Recent data also defines molecular mechanisms that may underlie the existing correlation between UPR activation and NAFLD. More interestingly, subsequent studies have demonstrated an additional mechanism, i.e. autophagy, to be involved in hepatic steatosis, and thus NAFLD pathogenesis, principally by regulating the insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. All these findings suggest possible mechanistic roles for autophagy in the progression of NAFLD and its complications. Both UPR and autophagy are dynamic and interconnected fluxes that act as protective responses to minimize the harmful effects of hepatic lipid accumulation, as well as the ER stress during NAFLD. The functions of UPR and autophagy in the liver, together with findings of decreased hepatic autophagy in correlation with conditions that predispose to NAFLD, such as obesity and aging, suggest that autophagy and UPR, alone or combined, may be novel therapeutic targets against the disease. In this review, we discuss the current evidence on the interplay between autophagy and the UPR in connection to the NAFLD pathogenesis.
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Affiliation(s)
- Zahra Dashti
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouria Kiani
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Motahareh Taghizadeh
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Maleki
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Borji
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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12
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Lu YY, Lu L, Ren HY, Hua W, Zheng N, Huang FY, Wang J, Tian M, Huang Q. The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes. ENVIRONMENT INTERNATIONAL 2024; 185:108532. [PMID: 38422876 DOI: 10.1016/j.envint.2024.108532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/02/2024] [Accepted: 02/22/2024] [Indexed: 03/02/2024]
Abstract
Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.
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Affiliation(s)
- Yan-Yang Lu
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China
| | - Lu Lu
- College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Hong-Yun Ren
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China
| | - Weizhen Hua
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou 350122, China
| | - Nengxing Zheng
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou 350122, China
| | - Fu-Yi Huang
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China
| | - Jiani Wang
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China
| | - Meiping Tian
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China
| | - Qingyu Huang
- Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China.
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13
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Liu W, Li M, Guo H, Wei S, Xu W, Yan Y, Shi Y, Xu Z, Chang K, Wei G, Zhao S. Single-cell transcriptome analysis of liver immune microenvironment changes induced by microplastics in mice with non-alcoholic fatty liver. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 912:168308. [PMID: 37977403 DOI: 10.1016/j.scitotenv.2023.168308] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
Recent studies have discovered that tiny particles of microplastics (MPs) at the nano-scale level can enter the body of organisms from the environment, potentially causing metabolic ailments. However, further investigation is required to understand the alterations in the immune microenvironment associated with non-alcoholic fatty liver disease (NAFLD) occurrence following exposure to MPs. Experiments were performed using mice, which were given a normal chow or high-fat diet (NCD or HFD, respectively) plus free drinking of sterile water with or without MPs, respectively. Employing an impartial technique known as unbiased single-cell RNA-sequencing (scRNA-seq), the cellular (single-cell) pathology landscape of NAFLD and related changes in the identified immune cell populations induced following MPs plus HFD treatment were assessed. The results showed that mice in the HFD groups had remarkably greater NAFLD activity scores than those from the NCD groups. Moreover, administration of MPs plus HFD further worsened the histopathological changes in the mice's liver, leading to hepatic steatosis, inflammatory cell infiltrations and ballooning degeneration. Following the construction of a sing-cell resolution transcriptomic atlas of 43,480 cells in the mice's livers of the indicated groups, clear cellular heterogeneity and potential cell-to-cell cross-talk could be observed. Specifically, we observed that MPs exacerbated the pro-inflammatory response and influenced the stemness of hepatocytes during HFD feeding. Importantly, treatment with MPs significantly increase the infiltration of the infiltrating liver-protecting Vsig4+ macrophages in the liver of the NAFLD mouse model while remarkably decreasing the angiogenic S100A6+ macrophage subpopulation. Furthermore, mice treated with MPs plus HFD exhibited significantly increased recruitment of CD4+ cells and heightened exhaustion of CD8+ T cells than those from the control group, characteristics typically associated with the dysregulation of immune homeostasis and severe inflammatory damage. Overall, this study offers valuable perspectives into comprehending the potential underlying cellular mechanisms and regulatory aspects of the microenvironment regarding MPs in the development of NAFLD.
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Affiliation(s)
- Wangrui Liu
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Meng Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huaqi Guo
- Department of Pulmonary and Critical Care Medicine, The Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Shiyin Wei
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yaoping Shi
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Kun Chang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Gang Wei
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
| | - Shuai Zhao
- Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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14
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Yao Z, Li X, Wang W, Ren P, Song S, Wang H, Xie Y, Li X, Li Z. Corn peptides attenuate non-alcoholic fatty liver disease via PINK1/Parkin-mediated mitochondrial autophagy. Food Nutr Res 2023; 67:9547. [PMID: 37808204 PMCID: PMC10552710 DOI: 10.29219/fnr.v67.9547] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/27/2023] [Accepted: 08/08/2023] [Indexed: 10/10/2023] Open
Abstract
Background Corn peptides, a novel food prepared from corn gluten meal (CGM) by enzymatic hydrolysis or microbial fermentation, have attracted considerable interest owing to their various bioactive properties. However, the underlying mechanism of corn peptides attenuate non-alcoholic fatty liver disease (NAFLD) remains unclear. Objective This study aimed to investigate the effect of corn peptides in NAFLD and to decipher the underlying mechanisms. Design NAFLD was induced by a high-fat diet (HFD) for 10 weeks. Corn peptides were administered during the period. Human hepatocellular carcinomas (HepG2) cells induced by free fatty acids were used for this mechanism study. Results Corn peptides alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, corn peptides blocked mitophagy suppression by HFD based on the increased LC3, ATG7 expressions, as well as decreased P62 levels. Corn peptides increased the expression of proteins involved in fatty acid β-oxidation, such as PPARα and PGC-1α. Corn peptides also improved the Ser/Thr kinase PINK1 (PINK1) and the E3 ubiquitin ligase Parkin (Parkin) translocation to mitochondria, which is confirmed by immunofluorescence. Furthermore, stable knockdown of PINK1 by PINK1 SiRNA in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Conclusion Corn peptides improved cell injury and ameliorated mitochondrial dysfunction and lipid accumulation via PINK1/Parkin-mediated autophagy in NAFLD. Thus, corn peptides could be a promising nutritional molecule with natural functions for preventing NAFLD.
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Affiliation(s)
- Zhicui Yao
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- College of Nursing, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Xiaoling Li
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- School of Nursing, Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Wentao Wang
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Peng Ren
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Shiming Song
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Haiyue Wang
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Ying Xie
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xingbo Li
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Zengning Li
- Department of Nutrition, Hebei Province Key Laboratory of Nutrition and Health, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
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15
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Chen J, Zheng D, Cai Z, Zhong B, Zhang H, Pan Z, Ling X, Han Y, Meng J, Li H, Chen X, Zhang H, Liu L. Increased DNMT1 Involvement in the Activation of LO2 Cell Death Induced by Silver Nanoparticles via Promoting TFEB-Dependent Autophagy. TOXICS 2023; 11:751. [PMID: 37755761 PMCID: PMC10537645 DOI: 10.3390/toxics11090751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/29/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023]
Abstract
The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 μg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 μg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.
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Affiliation(s)
- Jialong Chen
- Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China;
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Dongyan Zheng
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Ziwei Cai
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Bohuan Zhong
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Haiqiao Zhang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Zhijie Pan
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Xiaoxuan Ling
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Yali Han
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Jinxue Meng
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Huifang Li
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Xiaobing Chen
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - He Zhang
- Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China;
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
| | - Linhua Liu
- Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China;
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; (D.Z.); (Z.C.); (B.Z.); (H.Z.); (Z.P.); (X.L.); (Y.H.); (J.M.); (H.L.); (X.C.)
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Afshari H, Noori S, Zarghi A. Hepatic Steatosis Alleviated by a Novel Metformin and Quercetin Combination Activating Autophagy Through the cAMP/AMPK/SIRT1 Pathway. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2023; 22:e136952. [PMID: 38116565 PMCID: PMC10728872 DOI: 10.5812/ijpr-136952] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/09/2023] [Accepted: 05/28/2023] [Indexed: 12/21/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) incidence and prevalence are rapidly increasing globally. The combined effects of metformin and quercetin (Que) have yet to be investigated. However, both have demonstrated the potential to reduce triglyceride (TG) levels and treat NAFLD by promoting autophagy. The objective of the present study was to elucidate the mechanism of action and assess the role of autophagy in the lipid-lowering effects of Que, both individually and in combination with metformin, in a HepG2 cell model of hepatic steatosis. Triglyceride levels and lipogenic gene expression were reduced in HepG2 cells exposed to palmitic acid (PA) when treated with Que-metformin, as evidenced by triglyceride measurements and real-time PCR. The LDH release assay also showed that this combination induced autophagy to protect HepG2 cells from PA-induced cell death. According to the Western blot analysis outcomes, Que-metformin increased LC3-I and LC3-II protein levels while decreasing p62 expression to induce autophagy. In HepG2 cells, the co-administration of Que-metformin elevated cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels. Additionally, the inhibition of SIRT1 reversed the autophagy induced by Que-metformin. The findings of this study demonstrated for the first time that Que-metformin reduced hepatosteatosis by stimulating autophagy through the cAMP/AMPK/SIRT1 signaling pathway and diminishing inflammatory cytokines.
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Affiliation(s)
- Havva Afshari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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17
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Gu J, Kong A, Guo C, Liu J, Li K, Ren Z, Zhou Y, Tang M, Shi H. Cadmium perturbed lipid profile and induced liver dysfunction in mice through phosphatidylcholine remodeling and promoting arachidonic acid synthesis and metabolism. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 247:114254. [PMID: 36334344 DOI: 10.1016/j.ecoenv.2022.114254] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/23/2022] [Accepted: 10/29/2022] [Indexed: 06/16/2023]
Abstract
Cadmium ion (Cd2+) exposure has been reported to associate with the prevalence of dyslipidemia, and contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). However, Cd2+ exposure perturbed specific metabolic pathways and underlying mechanisms are still unclear. In the present study, through lipidomics analyses of differential metabolites in serum between the Cd2+-exposed mice and the control group, 179 differential metabolites were identified, among which phosphatidylcholines (PCs) accounted for 49 % metabolites. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment assay indicates that PCs participate in the metabolic pathways, including the Arachidonic Acid (AA) metabolism, which also could be potential NAFLD biomarkers. Moreover, in vivo and in vitro results suggested that Cd2+ exposure induced PC synthesis and remodeling, and increased AA level by promoting fatty acid desaturase 1 (FADS1) to catalyze synthesis process instead of cytosolic phospholipase A2 (cPLA2) mediated release pathway. Inhibition of FADS1 by T3364366 could reverse Cd-induced AA, prostaglandin E2 (PGE2) and triglyceride (TAG) levels, and it also reduce cisplatin resistance in HepG2 cells. This study provides new evidence of Cd2+-induced dyslipidemia and reveals underlying molecular mechanism involved in liver dysfunction of Cd2+ exposure.
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Affiliation(s)
- Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Anqi Kong
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Junlin Liu
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Zhen Ren
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Yang Zhou
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212000, China; School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212000, China.
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18
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Nasiri-Ansari N, Androutsakos T, Flessa CM, Kyrou I, Siasos G, Randeva HS, Kassi E, Papavassiliou AG. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells 2022; 11:2511. [PMID: 36010588 PMCID: PMC9407007 DOI: 10.3390/cells11162511] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Gerasimos Siasos
- Third Department of Cardiology, ‘Sotiria’ Thoracic Diseases General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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20
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Jia J, Liu R, Wei W, Yu F, Yu X, Shen Y, Chen C, Cai Z, Wang C, Zhao Z, Wang D, Yang L, Yuan G. Monocyte to High-Density Lipoprotein Cholesterol Ratio at the Nexus of Type 2 Diabetes Mellitus Patients With Metabolic-Associated Fatty Liver Disease. Front Physiol 2021; 12:762242. [PMID: 34975521 PMCID: PMC8718696 DOI: 10.3389/fphys.2021.762242] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022] Open
Abstract
Background: Recently, monocyte to high-density lipoprotein cholesterol ratio (MHR) as a novel inflammatory biomarker has drawn lots of attention. This study was conducted in patients with type 2 diabetes mellitus (T2DM) to investigate the correlation between MHR and metabolic-associated fatty liver disease (MAFLD). Methods: Totally, 1,051 patients with T2DM from the Affiliated Hospital of Jiangsu University were enrolled and classified as MAFLD (n = 745) group and non-MAFLD (n = 306) group according to the MAFLD diagnostic criteria. In contrast, patients were also separated into four groups based on MHR quartiles. Anthropometric and biochemical measurements were performed. The visceral fat area (VFA) and subcutaneous fat area (SFA) of participants were measured by dual bioelectrical impedance. Fatty liver was assessed by ultrasonography. Results: The MHR level of subjects in the MAFLD group was statistically greater than that in the non-MAFLD group (P < 0.05). Meanwhile, MHR was higher in the overweight or obese MAFLD group compared with that in the lean MAFLD group (P < 0.05). The area under the ROC Curve (AUC) assessed by MHR was larger than that of other inflammatory markers (P < 0.01). The cutoff value of MHR was 0.388, with a sensitivity of 61.74% and a specificity of 56.54%. For further study, binary logistic regression analyses of MAFLD as a dependent variable, the relationship between MHR and MAFLD was significant (P < 0.01). After adjusting for many factors, the relationship still existed. In the four groups based on MHR quartiles, groups with higher values of MHR had a significantly higher prevalence of MAFLD (P < 0.05). The percentage of patients with obese MAFLD increased as the MHR level increased (P < 0.01). Among different quartiles of MHR, it showed that with the increasing of MHR, the percentage of patients with MAFLD who had more than four metabolic dysfunction indicators increased, which was 46.39, 60.52, 66.79, and 79.91%, respectively, in each quartile. Conclusion: Monocyte to high-density lipoprotein cholesterol ratio is a simple and practicable inflammatory parameter that could be used for assessing MAFLD in T2DM. T2DM patients with higher MHR have more possibility to be diagnosed as MAFLD. Therefore, more attention should be given to the indicator in the examination of T2DM.
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Affiliation(s)
- Jue Jia
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ruoshuang Liu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Weiping Wei
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Fan Yu
- Department of Endocrinology and Metabolism, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
| | - Xiawen Yu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yirong Shen
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Caiqin Chen
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhensheng Cai
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chenxi Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhicong Zhao
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Dong Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ling Yang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guoyue Yuan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
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21
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Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns. Acta Pharm Sin B 2021; 11:3768-3778. [PMID: 35024305 PMCID: PMC8727918 DOI: 10.1016/j.apsb.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/24/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology. However, inheritance drives the ability to appropriately adapt to environmental stressors, and disease is the culmination of a maladaptive response. Thus “pure” genetic and “pure” xenobiotic liver diseases are modified by each other and other factors, identified or unknown. The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes. This exercise is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility. This review also discusses key new tools and approaches that will likely be critical to address this question in the future. Taken together, identifying the key gaps in our understanding is critical for the field to move forward, or at the very least to “know what we don't know.”
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Affiliation(s)
- Juliane I. Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, PA 15213, USA
- Corresponding authors.
| | - Gavin E. Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Corresponding authors.
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22
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Schnegelberger RD, Lang AL, Arteel GE, Beier JI. Environmental toxicant-induced maladaptive mitochondrial changes: A potential unifying mechanism in fatty liver disease? Acta Pharm Sin B 2021; 11:3756-3767. [PMID: 35024304 PMCID: PMC8727895 DOI: 10.1016/j.apsb.2021.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/29/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury. However, despite extensive evidence showing that exposure can lead to disease, current research approaches and regulatory policies fail to address the possibility that subtle changes caused by low level exposure to chemicals may also enhance preexisting conditions. In recent years, the conceptual understanding of the contribution of environmental chemicals to liver disease has progressed significantly. Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells, tissues, and organs. Here, we review persistent maladaptive changes to mitochondria in response to environmental toxicant exposure as a mechanism of hepatotoxicity. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease, rational targeted therapy can be developed to better predict risk, as well as to treat or prevent this disease.
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Affiliation(s)
- Regina D. Schnegelberger
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Anna L. Lang
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Gavin E. Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Juliane I. Beier
- Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA
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23
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Ning B, Guo C, Kong A, Li K, Xie Y, Shi H, Gu J. Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease. Cells 2021; 10:cells10113204. [PMID: 34831428 PMCID: PMC8622220 DOI: 10.3390/cells10113204] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/09/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.
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Affiliation(s)
- Bo Ning
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Anqi Kong
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Yimin Xie
- Affiliated Hospital of Jiangsu University—Yixing Hospital, Yixing 214200, China;
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- Correspondence: ; Tel.: +86-0511-88791923
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Posidonia oceanica (L.) Delile Extract Reduces Lipid Accumulation through Autophagy Activation in HepG2 Cells. Pharmaceuticals (Basel) 2021; 14:ph14100969. [PMID: 34681193 PMCID: PMC8540819 DOI: 10.3390/ph14100969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
Posidonia oceanica (L.) Delile is a marine plant traditionally used as an herbal medicine for various health disorders. P. oceanica leaf extract (POE) has been shown to be a phytocomplex with cell-safe bioactivities, including the ability to trigger autophagy. Autophagy is a key pathway to counteract non-alcoholic fatty liver disease (NAFLD) by controlling the breakdown of lipid droplets in the liver. The aim of this study was to explore the ability of POE to trigger autophagy and reduce lipid accumulation in human hepatoma (HepG2) cells and then verify the possible link between the effect of POE on lipid reduction and autophagy activation. Expression levels of autophagy markers were monitored by the Western blot technique in POE-treated HepG2 cells, whereas the extent of lipid accumulation in HepG2 cells was assessed by Oil red O staining. Chloroquine (CQ), an autophagy inhibitor, was used to study the relationship between POE-induced autophagy and intracellular lipid accumulation. POE was found to stimulate an autophagy flux over time in HepG2 cells by lowering the phosphorylation state of ribosomal protein S6, increasing Beclin-1 and LC3-II levels, and decreasing p62 levels. By blocking autophagy with CQ, the effect of POE on intracellular lipid accumulation was clearly reversed, suggesting that the POE phytocomplex may reduce lipid accumulation in HepG2 cells by activating the autophagic process. This work indicates that P. oceanica may be considered as a promising molecule supplier to discover new natural approaches for the management of NAFLD.
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