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Choudhuri S, Garg NJ. Hepatocyte Nuclear Factor 4 Alpha: A Key Regulator of Liver Disease Pathology and Haemostatic Disorders. Liver Int 2025; 45:e16245. [PMID: 40387433 DOI: 10.1111/liv.16245] [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: 08/15/2024] [Revised: 12/19/2024] [Accepted: 01/03/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVE Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte differentiation in fetal and adult liver and exerts its transcriptional role in determining physiological functions of the liver. The objective of this review is to address the current knowledge of molecular mechanisms involved in HNF4α regulation in multiple aspects of liver disease pathogenesis. METHODS Based on available literature, this review summarises the current state of knowledge onthe mechanism of HNF4α dysregulation, and the role of HNF4α activity inregulating early to advanced stages of various liver diseases. RESULTS Patients with deranged HNF4α expression are at higher risk for the development of liver diseases such as viral hepatitis, alcoholic/nonalcoholic fatty liver disease, hepatocellular carcinoma, and haematological disorders such as coagulopathy and bleeding disorders. DISCUSSION HNF4α interactions with nuclear receptors and target genes promote liver disease pathology by regulating various metabolic pathways. The strong correlation between deranged HNF4α expression and the severity of liver diseases suggests that targeting HNF4α expression can offer potential therapeutic strategy in the prevention of liver disease pathology and haemostatic disorders.
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Affiliation(s)
- Subhadip Choudhuri
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
| | - Nisha Jain Garg
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
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Wang X, Shao Y, Yang Z, Yang H, Wang Z. Role of Vanin-1 Gene Methylation in Fat Synthesis in Goose Liver: Effects of Betaine and 5-Azacytidine Treatments. Animals (Basel) 2025; 15:719. [PMID: 40076002 PMCID: PMC11899362 DOI: 10.3390/ani15050719] [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: 12/20/2024] [Revised: 02/18/2025] [Accepted: 03/01/2025] [Indexed: 03/14/2025] Open
Abstract
This study aimed to investigate the mediating effect of vanin-1 (VNN1) and its DNA methylation on the reduction in liver fat synthesis due to the role of betaine and 5-Azacytidine (5-AZA) in geese. Twenty-eight 35-day-old male Jiangnan white geese with similar body weight (BW) and good health conditions were randomized into four groups (seven birds per group). All the birds were housed with the same type of basal diet. The control group was treated with normal saline intraperitoneally (I.P.); the AZA group was treated I.P. with AZA (2 mg/kg); the betaine group was fed with betaine through the diet and treated I.P. with normal saline (1.2 g/kg); the AZA+betaine group was fed with betaine through the diet and treated I.P. with AZA. The results showed that the administration of AZA significantly increased serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and VNN1 enzyme activity (p < 0.05); additionally, the expression levels of the molecules in various tissues were up-regulated to different extents, such as VNN1, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl-CoA dehydrogenase (SCD), and sterol regulatory element binding protein (SREBP); in contrast, the treatment of betaine reduced serum TC levels and the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio; furthermore, hepatic DNA methylation in the AZA group was decreased in terms of the VNN1 promoter region. The results demonstrated that the expression of the VNN1 gene was negatively correlated with DNA methylation. This finding verified the key role of VNN1 and its methylation in the inhibition of liver lipid synthesis by betaine and provided a novel molecular mechanism for the regulation of liver lipid metabolism.
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Affiliation(s)
| | | | - Zhi Yang
- Correspondence: ; Tel.: +86-514-87979045; Fax: +86-514-87990256
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Zheng K, Yang L, Zhang RS, Qian YH, Zhou YG, Huang WF, Lin JC, Shi YJ, Kong XN. Puerarin Alleviates Alcoholic Liver Disease via Suppressing Lipolysis Induced by Sympathetic Outflow. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:863-888. [PMID: 40374377 DOI: 10.1142/s0192415x25500326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2025]
Abstract
The aim of this study was to evaluate the therapeutic effect of puerarin (PUE) on alcoholic liver disease (ALD) and elucidate the potential mechanism from the perspective of lipolysis and hepatic steatosis. Assessment of PUE efficacy against ALD was performed using serum biochemical parameters and the histological examination of liver and adipose tissue via Hematoxylin and eosin (H&E) staining. The potential mechanisms underlying the amelioration of ALD by PUE were investigated using Western blotting (WB) analysis and immunofluorescence (IHC) staining. We demonstrated that PUE attenuated steatosis in ALD by alleviating ethanol-induced liver damage and lipid accumulation, suppressing the expression of lipid synthesis genes, upregulating the expression of lipid metabolism genes, and reducing lipolysis by inhibiting adipose triglyceride lipase (ATGL) activation and the phosphorylation of hormone-sensitive lipase (HSL). In conclusion, PUE ameliorates ALD by inhibiting the sympathetic outflow-mediated activation of key lipolysis enzymes ATGL and HSL. These findings provide a solid theoretical foundation for the potential application of PUE in the clinical treatment of ALD.
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Affiliation(s)
- Ke Zheng
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Liu Yang
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rui-Shuo Zhang
- Clinical Medicine Admitted Class of 2020, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, China
| | - Yi-Han Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu-Ge Zhou
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Fan Huang
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Cheng Lin
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Jun Shi
- Abdominal Transplantation Center, General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Xiao-Ni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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4
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Choi YJ, Kim Y, Hwang S. Role of Neutrophils in the Development of Steatotic Liver Disease. Semin Liver Dis 2024; 44:300-318. [PMID: 39117322 DOI: 10.1055/s-0044-1789207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.
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Affiliation(s)
- You-Jin Choi
- College of Pharmacy, Daegu Catholic University, Gyeongsan, Republic of Korea
| | - Yeonsoo Kim
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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5
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Kang S, Koh JM, Im DS. N-3 Polyunsaturated Fatty Acids Protect against Alcoholic Liver Steatosis by Activating FFA4 in Kupffer Cells. Int J Mol Sci 2024; 25:5476. [PMID: 38791514 PMCID: PMC11122576 DOI: 10.3390/ijms25105476] [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: 04/08/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and Ffa4 knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in Ffa4 KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis.
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Affiliation(s)
- Saeromi Kang
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea;
| | - Jung-Min Koh
- Division of Endocrinology and Metabolism, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 05505, Republic of Korea;
| | - Dong-Soon Im
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea;
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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7
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Zhu W, Chen M, Wang Y, Chen Y, Zhang Y, Wang Y, Liu P, Li P. Regulation of renal lipid deposition in diabetic nephropathy on morroniside via inhibition of NF-KB/TNF-a/SREBP1c signaling pathway. Chem Biol Interact 2023; 385:110711. [PMID: 37769864 DOI: 10.1016/j.cbi.2023.110711] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/31/2023] [Accepted: 09/11/2023] [Indexed: 10/03/2023]
Abstract
Morroniside (MOR), a cyclic enol ether terpene glycoside isolated from Cornus officinalis, has been shown to inhibit lipid accumulation, although the mechanism of action is uncertain. The aim of this study was to investigate the potential pathways by which MOR affects renal lipid deposition in diabetic nephropathy (DN). In vitro and in vivo experiments were performed using the PA-induced HK-2 cell model and a KKAy animal model, respectively. Network pharmacological analysis was used to identify potential MOR signaling pathways for DN therapy, with results verified via Western blotting and immunofluorescence experiments. The effect of MOR on lipid metabolism was investigated using BODIPY 493/503 staining. Our results indicate that MOR significantly reduces lipid accumulation both in vitro and in vivo. According to network pharmacology studies, the NF-κB/TNF-α/SREBP1c signaling pathway may be the mechanism of action of MOR in DN. MOR was found to inhibit this pathway by reducing the phosphorylation of NF-κB p65 and the expression of TNF-α and SREBP1c, similar to the effects of Bay11-7082. Additionally, MOR significantly inhibited the expression of lipid factors such as ACC, FAS, and SCD1. In conclusion, MOR can regulate the disruption of lipid metabolism in DN and reduce renal lipid deposition via suppression of the NF-κB/TNF-α/SREBP1c signaling pathway.
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Affiliation(s)
- Wenhui Zhu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Ming Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yang Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yao Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yonggang Zhang
- First People's Hospital of Qiqihaer City, Heilongjiang Province, China
| | - Yan Wang
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, China.
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Shreya S, Grosset CF, Jain BP. Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review. Int J Mol Sci 2023; 24:14066. [PMID: 37762367 PMCID: PMC10531763 DOI: 10.3390/ijms241814066] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/04/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR-IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)-modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.
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Affiliation(s)
- Smriti Shreya
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India;
| | - Christophe F. Grosset
- MIRCADE Team, U1312, Bordeaux Institute in Oncology, BRIC, Université de Bordeaux, 146 Rue Léo Saignat, F-33000 Bordeaux, France
| | - Buddhi Prakash Jain
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India;
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Wang Y, Chen Q, Wu S, Sun X, Yin R, Ouyang Z, Yin H, Wei Y. Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1. Acta Pharm Sin B 2023; 13:3906-3918. [PMID: 37719371 PMCID: PMC10502278 DOI: 10.1016/j.apsb.2023.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/16/2022] [Accepted: 12/10/2022] [Indexed: 09/19/2023] Open
Abstract
Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
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Affiliation(s)
- Yalan Wang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qiubing Chen
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Shuang Wu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xinyu Sun
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hao Yin
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- RNA Institute, Wuhan University, Wuhan 430072, China
- Wuhan Research Centre for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430010, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
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Lan R, Luo H, Wu F, Wang Y, Zhao Z. Chitosan Oligosaccharides Alleviate Heat-Stress-Induced Lipid Metabolism Disorders by Suppressing the Oxidative Stress and Inflammatory Response in the Liver of Broilers. Antioxidants (Basel) 2023; 12:1497. [PMID: 37627493 PMCID: PMC10451627 DOI: 10.3390/antiox12081497] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/21/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Heat stress has been reported to induce hepatic oxidative stress and alter lipid metabolism and fat deposition in broilers. Chitosan oligosaccharides (COSs), a natural oligosaccharide, has anti-oxidant, anti-inflammatory, and lipid-lowering effects. This study is conducted to evaluate dietary COS supplementation on hepatic anti-oxidant capacity, inflammatory response, and lipid metabolism in heat-stressed broilers. The results indicate that heat-stress-induced poor (p < 0.05) growth performance and higher (p < 0.05) abdominal adiposity are alleviated by COS supplementation. Heat stress increases (p < 0.05) serum AST and ATL activity, serum and liver MDA, TG, TC, and LDL-C levels, and the expression of hepatic IL-1β, IL-6, SREBP-1c, ACC, and FAS, while it decreases (p < 0.05) serum SOD and CAT activity, liver GSH-Px and SOD activity, and the expression of hepatic Nrf2, GPX1, IL-10, MTTP, PPARα, and CPT1. Nevertheless, COS supplementation decreases (p < 0.05) serum AST and ATL activity, serum and liver MDA, TG, TC, and LDL-C levels, and the expression of hepatic IL-1β, IL-6, SREBP-1c, ACC, and FAS, while it increases (p < 0.05) serum SOD and CAT activity, liver GSH-Px activity, and the expression of hepatic Nrf2, CAT, IL-10, LPL, MTTP, PPARα, and CPT1. In conclusion, COS could alleviate heat-stress-induced lipid metabolism disorders by enhancing hepatic anti-oxidant and anti-inflammatory capacity.
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Affiliation(s)
| | | | | | | | - Zhihui Zhao
- Department of Animal Science and Technology, College of Coastal Agriculture Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (R.L.); (H.L.); (F.W.); (Y.W.)
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Gao H, Li Z, Liu Y, Zhao YK, Cheng C, Qiu F, Gao Y, Lu YW, Song XH, Wang JB, Ma ZT. A clinical experience-based Chinese herbal formula improves ethanol-induced drunken behavior and hepatic steatohepatitis in mice models. Chin Med 2023; 18:47. [PMID: 37127639 PMCID: PMC10150545 DOI: 10.1186/s13020-023-00753-5] [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: 02/06/2023] [Accepted: 04/13/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Bao-Gan-Xing-Jiu-Wan (BGXJW) is a clinical experience-based Chinese herbal formula. Its efficacy, pharmacological safety, targeted function, process quality, and other aspects have met the evaluation standards and the latest requirements of preparations. It could prevent and alleviate the symptoms of drunkenness and alcoholic liver injury clinically. The present work aims to elucidate whether BGXJW could protect against drunkenness and alcoholic liver disease in mice and explore the associated mechanism. MATERIAL AND METHODS We used acute-on-chronic (NIAAA) mice model to induce alcoholic steatosis, and alcohol binge-drinking model to reappear the drunk condition. BGXJW at indicated doses were administered by oral gavage respectively to analyze its effects on alcoholic liver injury and the associated molecular mechanisms. RESULTS BGXJW had no cardiac, hepatic, renal, or intestinal toxicity in mice. Alcoholic liver injury and steatosis in the NIAAA mode were effectively prevented by BGXJW treatment. BGXJW increased the expression of alcohol metabolizing enzymes ADH, CYP2E1, and ALDH2 to enhance alcohol metabolism, inhibited steatosis through regulating lipid metabolism, counteracted alcohol-induced upregulation of lipid synthesis related proteins SREBP1, FASN, and SCD1, meanwhile it enhanced fatty acids β-oxidation related proteins PPAR-α and CPT1A. Alcohol taken enhanced pro-inflammatory TNF-α, IL-6 and down-regulated the anti-inflammatory IL-10 expression in the liver, which were also reversed by BGXJW administration. Moreover, BGXJW significantly decreased the blood ethanol concentration and alleviated drunkenness in the alcohol binge-drinking mice model. CONCLUSIONS BGXJW could effectively relieve drunkenness and prevent alcoholic liver disease by regulating lipid metabolism, inflammatory response, and alcohol metabolism.
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Affiliation(s)
- Han Gao
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Hepatology, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Zhen Li
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- College of Pharmacy, Henan University of Traditional Chinese Medicine, Henan, 450046, Zhengzhou, China
| | - Yao Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Infectious Disease, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
| | - Yong-Kang Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Cheng
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
- Department of Pharmacy, Jincheng General Hospital, Jincheng, 048006, Shanxi, China
| | - Feng Qiu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Yuan Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Ya-Wen Lu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Xin-Hua Song
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Jia-Bo Wang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China.
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Zhi-Tao Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
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Patel D, Rathaur P, Parwani K, Patel F, Sharma D, Johar K, Mandal P. In vitro, in vivo, and in silico analysis of synbiotics as preventive interventions for lipid metabolism in ethanol-induced adipose tissue injury. Lipids Health Dis 2023; 22:49. [PMID: 37055787 PMCID: PMC10103406 DOI: 10.1186/s12944-023-01809-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/23/2023] [Indexed: 04/15/2023] Open
Abstract
The risk of alcoholic liver disease (ALD) is increased by excessive ethanol drinking. For the prevention of ALD, the effects of ethanol on the liver, adipose tissue, and gut are crucial. Interestingly, garlic and a few probiotic strains can protect against ethanol-induced hepatotoxicity. However, the relationship between adipose tissue inflammation, Kyolic aged garlic extract (AGE), and Lactobacillus rhamnosus MTCC1423 in developing ALD is unknown. Therefore, the present study explored the effect of synbiotics (a combination of prebiotics and probiotics) on adipose tissue to prevent ALD. To investigate the efficacy of synbiotics administration on adipose tissue in preventing ALD, in vitro (3T3-L1 cells, N = 3) groups: control, control + LPS (lipopolysaccharide), ethanol, ethanol + LPS, ethanol + synbiotics, ethanol + synbiotics + LPS; in vivo (Wistar male rats, N = 6) groups: control, ethanol, pairfed, ethanol + synbiotics and in silico experiments were conducted. Lactobacillus multiplies in accordance with the growth curve when exposed to AGE. Additionally, Oil red O staining and scanning electron microscopy (SEM) demonstrated that synbiotics therapy maintained the morphology of adipocytes in the alcoholic model. In support of the morphological changes, quantitative real-time PCR demonstrated overexpression of adiponectin and downregulation of leptin, resistin, PPARγ, CYP2E1, iNOS, IL-6, and TNF-α after administration of synbiotics compared to the ethanol group. In addition, MDA estimation by high-performance liquid chromatography (HPLC) indicated that the synbiotics treatment reduced oxidative stress in rat adipose tissue. Consequently, the in-silico analysis revealed that AGE inhibited the C-D-T networks as PPARγ acting as the main target protein. The current study demonstrates that using synbiotics improves adipose tissue metabolism in ALD.
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Affiliation(s)
- Dhara Patel
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa-388421 Gujarat, India
| | - Pooja Rathaur
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat India
| | - Kirti Parwani
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa-388421 Gujarat, India
| | - Farhin Patel
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa-388421 Gujarat, India
| | - Dixa Sharma
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa-388421 Gujarat, India
| | - Kaid Johar
- Department of Zoology, Biomedical Technology, and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, 380009 Gujarat India
| | - Palash Mandal
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa-388421 Gujarat, India
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13
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Salama RM, Abbas SS, Darwish SF, Sallam AA, Elmongy NF, El Wakeel SA. Regulation of NOX/p38 MAPK/PPARα pathways and miR-155 expression by boswellic acids reduces hepatic injury in experimentally-induced alcoholic liver disease mouse model: novel mechanistic insight. Arch Pharm Res 2023; 46:323-338. [PMID: 36959348 PMCID: PMC10123034 DOI: 10.1007/s12272-023-01441-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/28/2023] [Indexed: 03/25/2023]
Abstract
Alcoholic liver disease (ALD) refers to hepatic ailments induced by excessive alcohol intake. The pathogenesis of ALD comprises a complex interplay between various mechanistic pathways, among which inflammation and oxidative stress are key players. Boswellic acids (BAs), found in Boswellia serrata, have shown hepatoprotective effects owing to their antioxidant and anti-inflammatory activities, nevertheless, their therapeutic potential against ALD has not been previously investigated. Hence, this study was performed to depict the possible protective effect of BAs and detect their underlying mechanism of action in an experimentally-induced ALD mouse model. Male BALB/c mice were equally categorized into six groups: control, BAs-treated, ALD, and ALD that received BAs at three-dose levels (125, 250, and 500 mg/kg) by oral gavage for 14 days. Results showed that the high dose of BAs had the most protective impact against ALD according to histopathology examination, blood alcohol concentration (BAC), and liver function enzymes. Mechanistic investigations revealed that BAs (500 mg/kg) caused a significant decrease in cytochrome P450 2E1(CYP2E1), nicotine adenine dinucleotide phosphate oxidase (NOX) 1/2/4, p38 mitogen-activated protein kinase (MAPK), and sterol regulatory element-binding protein-1c (SREBP-1c) levels, and the expression of miR-155, yet increased peroxisome proliferator-activated receptor alpha (PPARα) levels. This led to an improvement in lipid profile and reduced hepatic inflammation, oxidative stress, and apoptosis indices. In summary, our study concludes that BAs can protect against ethanol-induced hepatic injury, via modulating NOX/p38 MAPK/PPARα pathways and miR-155 expression.
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Affiliation(s)
- Rania M Salama
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), KM 28, Cairo-Ismailia Road, Ahmed Orabi District, Cairo, Egypt.
| | - Samah S Abbas
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), KM 28, Cairo-Ismailia Road, Ahmed Orabi District, Cairo, Egypt
| | - Samar F Darwish
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Al Aliaa Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Noura F Elmongy
- Physiology Department, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Sara A El Wakeel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), KM 28, Cairo-Ismailia Road, Ahmed Orabi District, Cairo, Egypt
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14
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Guo R, Chen L, Zhu J, Li J, Ding Q, Chang K, Han Q, Li S. Monounsaturated fatty acid-enriched olive oil exacerbates chronic alcohol-induced hepatic steatosis and liver injury in C57BL/6J mice. Food Funct 2023; 14:1573-1583. [PMID: 36655918 DOI: 10.1039/d2fo03323b] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Dietary oil composition determines the pathological processes of alcoholic fatty liver disease (AFLD). Oil rich in saturated fatty acids protects, whereas oil rich in polyunsaturated fatty acids aggravates the alcohol-induced liver injury. However, limited studies have been conducted to address how monounsaturated fatty acids (MUFAs) enriched oil controls the pathological development of AFLD. Therefore, this study was designed to evaluate the effect of MUFA-enriched extra virgin olive oil (OO) on AFLD. Twenty C57BL/6J mice were randomly allocated into four groups and fed modified Lieber-DeCarli liquid diets containing isocaloric maltose dextrin a non-alcohol or alcohol with corn oil and OO for four weeks. Dietary OO significantly exacerbated alcohol-induced liver dysfunction, evidenced by histological examinations and disturbed biochemical parameters. Dietary OO with alcohol decreased hormone-sensitive lipase (HSL), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), and carnitine palmitoyltransferase-Iα (CPT1α) expression, and increased sterol regulatory element-binding protein-1c (SREBP-1c), diacylglycerol acyltransferase-2 (DGAT2), and very low-density lipoprotein receptor (VLDLR) expression in the liver. It also promoted the expression of hepatic interleukin-6 (IL-6) and hepatic tumour necrosis factor-alpha (TNF-α) at the transcriptional level. Additionally, adipose tissue lipolysis partially had an etiologic effect on alcohol-induced hepatic steatosis under OO pretreatment. In conclusion, MUFA-enriched OO exacerbated liver dysfunction in vivo. OO should be cautiously considered as a unique dietary oil source for individuals with AFLD.
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Affiliation(s)
- Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. .,Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Lin Chen
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Jinyan Zhu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Jiaomei Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. .,Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Qingchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Kaixin Chang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Qiang Han
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. .,Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. .,Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
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15
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Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges. Therap Adv Gastroenterol 2023; 16:17562848231170946. [PMID: 37187673 PMCID: PMC10176580 DOI: 10.1177/17562848231170946] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.
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Affiliation(s)
- Ayooluwatomiwa Deborah Adekunle
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
| | - Adeyinka Adejumo
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
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16
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Awadh AA. The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release. BIOMED RESEARCH INTERNATIONAL 2023; 2023:5156601. [PMID: 37090186 PMCID: PMC10121354 DOI: 10.1155/2023/5156601] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 04/25/2023]
Abstract
The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.
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Affiliation(s)
- Abdullah A. Awadh
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah 21423, Saudi Arabia
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17
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Jung H, You S, Choi SI, Kang CH, Kim GH. Levilactobacillus brevis MG5311 Alleviates Ethanol-Induced Liver Injury by Suppressing Hepatic Oxidative Stress in C57BL/6 Mice. Microorganisms 2022; 10:microorganisms10122488. [PMID: 36557739 PMCID: PMC9781832 DOI: 10.3390/microorganisms10122488] [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: 11/18/2022] [Revised: 12/01/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Alcoholic liver disease (ALD), caused by excessive alcohol consumption, leads to high mortality. We investigated the hepatoprotective effect of Levilactobacillus brevis MG5311 in C57BL/6 mice with liver injuries induced by chronic ethanol plus binge feeding. L. brevis MG5311 was administered orally at a dose of 1 × 109 CFU/mouse once daily for 32 days. L. brevis MG5311 administration significantly reduced serum ALT, AST, and triglyceride (TG) levels in ethanol-fed mice. L. brevis MG5311 also decreased malondialdehyde levels and increased glutathione peroxidase (GPx) activity in liver tissues. In addition, hepatic TG content and histopathological scores were significantly reduced. L. brevis MG5311 increased the protein expression of SIRT1, PPARα, SOD1, CAT, and GPx 1/2 in liver tissue, while inhibiting CYP2E1 and SREBP-1c. These results indicated that L. brevis MG5311 alleviated ethanol-induced liver injury by inhibiting hepatic oxidative stress and promoting lipid metabolism. Therefore, L. brevis MG5311 may be a useful probiotic candidate for ameliorating or preventing ALD.
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Affiliation(s)
- Hyunna Jung
- Department of Bio-Health Convergence, Duksung Women’s University, Seoul 01369, Republic of Korea
| | - Sohyeon You
- Department of Bio-Health Convergence, Duksung Women’s University, Seoul 01369, Republic of Korea
| | - Soo-Im Choi
- Department of Bio-Health Convergence, Duksung Women’s University, Seoul 01369, Republic of Korea
- MEDIOGEN, Co., Ltd., Biovalley 1-ro, Jecheon-si 27159, Republic of Korea
- Correspondence: (S.-I.C.); (G.-H.K.); Tel.: +82-2-901-8662 (S.-I.C.); +82-2-901-8496 (G.-H.K.)
| | - Chang-Ho Kang
- MEDIOGEN, Co., Ltd., Biovalley 1-ro, Jecheon-si 27159, Republic of Korea
| | - Gun-Hee Kim
- Department of Food and Nutrition, Duksung Women’s University, Seoul 01369, Republic of Korea
- Correspondence: (S.-I.C.); (G.-H.K.); Tel.: +82-2-901-8662 (S.-I.C.); +82-2-901-8496 (G.-H.K.)
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18
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Garcia J, Chang R, Steinberg RA, Arce A, Yang J, Van Der Eb P, Abdullah T, Chandrashekar DV, Eck SM, Meza P, Liu ZX, Cadenas E, Cribbs DH, Kaplowitz N, Sumbria RK, Han D. Modulation of hepatic amyloid precursor protein and lipoprotein receptor-related protein 1 by chronic alcohol intake: Potential link between liver steatosis and amyloid-β. Front Physiol 2022; 13:930402. [PMID: 36187787 PMCID: PMC9520570 DOI: 10.3389/fphys.2022.930402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer’s disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver that removes Aβ from blood and peripheral organs, and 2) alcohol significantly upregulated APP (∼2-fold), a potentially important source of Aβ in the periphery and brain. The decrease in hepatic LRP1 and increase in hepatic APP likely switches the liver from being a remover or low producer of Aβ to an important source of Aβ in the periphery, which can impact the brain. The downregulation of LRP1 and upregulation of APP in the liver was observed in the first week of intragastric alcohol feeding, and also occurred in other alcohol feeding models (NIAAA binge alcohol model and intragastric alcohol feeding to rats). Modulation of hepatic LRP1 and APP does not seem alcohol-specific, as ob/ob mice with significant steatosis also had declines in LRP1 and increases in APP expression in the liver. These findings suggest that liver steatosis rather than alcohol-induced liver injury is likely responsible for regulation of hepatic LRP1 and APP. Both obesity and alcohol intake have been linked to AD and our data suggests that liver steatosis associated with these two conditions modulates hepatic LRP1 and APP to disrupt Aβ processing by the liver to promote AD.
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Affiliation(s)
- Jerome Garcia
- Department of Biology, University of La Verne, Verne, CA, United States
| | - Rudy Chang
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
| | - Ross A. Steinberg
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
| | - Aldo Arce
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
| | - Joshua Yang
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
| | - Peter Van Der Eb
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
| | - Tamara Abdullah
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
| | - Devaraj V. Chandrashekar
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
| | - Sydney M. Eck
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
| | - Pablo Meza
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
| | - Zhang-Xu Liu
- Department of Molecular Microbiology and Immunology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Enrique Cadenas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - David H. Cribbs
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
| | - Neil Kaplowitz
- University of Southern California Research Center for Liver Diseases and Southern California Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rachita K. Sumbria
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
- Department of Neurology, University of California, Irvine, Irvine, CA, United States
| | - Derick Han
- School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States
- *Correspondence: Derick Han,
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19
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Abstract
The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.
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20
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Ferdouse A, Clugston RD. Pathogenesis of Alcohol-Associated Fatty Liver: Lessons From Transgenic Mice. Front Physiol 2022; 13:940974. [PMID: 35864895 PMCID: PMC9294393 DOI: 10.3389/fphys.2022.940974] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 12/18/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol’s known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol’s effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol’s effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.
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21
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Shafqat M, Jo JH, Moon HH, Choi YI, Shin DH. Alcohol-related liver disease and liver transplantation. KOSIN MEDICAL JOURNAL 2022. [DOI: 10.7180/kmj.22.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Alcohol-related liver disease (ALD) has become the major cause of liver transplantation (LT) in Korea, and is currently the most common cause of LT in Europe and the United States. Although, ALD is one of the most common indications for LT, it is traditionally not considered as an option for patients with ALD due to organ shortages and concerns about relapse. To select patients with terminal liver disease due to ALD for transplants, most LT centers in the United States and European countries require a 6-month sober period before transplantation. However, Korea has a different social and cultural background than Western countries, and most organ transplants are made from living donors, who account for approximately twice as many procedures as deceased donors. Most LT centers in Korea do not require a specific period of sobriety before transplantation in patients with ALD. As per the literature, 8%–20% of patients resume alcohol consumption 1 year after LT, and this proportion increases to 30%–40% at 5 years post-LT, among which 10%–15% of patients resume heavy drinking. According to previous studies, the risk factors for alcohol relapse after LT are as follows: young age, poor familial and social support, family history of alcohol use disorder, previous history of alcohol-related treatment, shorter abstinence before LT, smoking, psychiatric disorders, irregular follow-up, and unemployment. Recognition of the risk factors, early detection of alcohol consumption after LT, and regular follow-up by a multidisciplinary team are important for improving the short- and long-term outcomes of LT patients with ALD.
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22
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Charkoftaki G, Tan WY, Berrios-Carcamo P, Orlicky DJ, Golla JP, Garcia-Milian R, Aalizadeh R, Thomaidis NS, Thompson DC, Vasiliou V. Liver metabolomics identifies bile acid profile changes at early stages of alcoholic liver disease in mice. Chem Biol Interact 2022; 360:109931. [PMID: 35429548 PMCID: PMC9364420 DOI: 10.1016/j.cbi.2022.109931] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/30/2022] [Accepted: 04/03/2022] [Indexed: 12/18/2022]
Abstract
Alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. The liver sustains the earliest and the greatest degree of tissue injury due to chronic alcohol consumption and it has been estimated that alcoholic liver disease (ALD) accounts for almost 50% of all deaths from cirrhosis in the world. In this study, we used a modified Lieber-DeCarli (LD) diet to treat mice with alcohol and simulate chronic alcohol drinking. Using an untargeted metabolomics approach, our aim was to identify the various metabolites and pathways that are altered in the early stages of ALD. Histopathology showed minimal changes in the liver after 6 weeks of alcohol consumption. However, untargeted metabolomics analyses identified 304 metabolic features that were either up- or down-regulated in the livers of ethanol-consuming mice. Pathway analysis revealed significant alcohol-induced alterations, the most significant of which was in the FXR/RXR activation pathway. Targeted metabolomics focusing on bile acid biosynthesis showed elevated taurine-conjugated cholic acid compounds in ethanol-consuming mice. In summary, we showed that the changes in the liver metabolome manifest very early in the development of ALD, and when minimal changes in liver histopathology have occurred. Although alterations in biochemical pathways indicate a complex pathology in the very early stages of alcohol consumption, bile acid changes may serve as biomarkers of the early onset of ALD.
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Affiliation(s)
- Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Wan Ying Tan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Pablo Berrios-Carcamo
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA; Center for Regenerative Medicine, Faculty of Medicine Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
| | - David J Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Jaya Prakash Golla
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Rolando Garcia-Milian
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA; Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale School of Medicine, New Haven, CT, 06210, USA
| | - Reza Aalizadeh
- Laboratory of Analytical Chemistry, Department of Chemistry, National Kapodistrian University of Athens University Campus, Zografou, 15771, Athens, Greece
| | - Nikolaos S Thomaidis
- Laboratory of Analytical Chemistry, Department of Chemistry, National Kapodistrian University of Athens University Campus, Zografou, 15771, Athens, Greece
| | - David C Thompson
- Department of Clinical Pharmacy, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.
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23
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Baicalin ameliorates alcohol-induced hepatic steatosis by suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL. Arch Biochem Biophys 2022; 722:109236. [DOI: 10.1016/j.abb.2022.109236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/17/2022] [Accepted: 04/11/2022] [Indexed: 11/15/2022]
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24
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Liu SX, Liu H, Wang S, Zhang CL, Guo FF, Zeng T. Diallyl disulfide ameliorates ethanol-induced liver steatosis and inflammation by maintaining the fatty acid catabolism and regulating the gut-liver axis. Food Chem Toxicol 2022; 164:113108. [PMID: 35526736 DOI: 10.1016/j.fct.2022.113108] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/12/2022] [Accepted: 04/30/2022] [Indexed: 12/18/2022]
Abstract
Diallyl disulfide (DADS) has been suggested to possess hepatoprotection against alcoholic liver disease (ALD) by a couple of pilot studies, while the underlying mechanisms remain largely unknown. This study aimed to investigate the hepatoprotective effects of DADS against ethanol-induced liver steatosis and early inflammation by using the chronic-plus-binge mice model and cultured J774A.1 macrophages and AML12 hepatocytes. We found that DADS significantly attenuated ethanol-induced elevation of serum aminotransferase activities, accumulation of liver triglyceride, hepatocytes apoptosis, oxidative stress, infiltration of macrophages and neutrophils, and proinflammatory polarization of macrophages in mice livers. In addition, chronic-plus-binge drinking induced apparent intestinal mucosa damage and disturbance of gut microbiota, endotoxemia, and activation of hepatic NF-κB signaling and NLRP3 inflammasome, which was inhibited by DADS. In vitro studies using cocultured AML12/J774A.1 cells showed that DADS suppressed ethanol/LPS-induced cell injury and inflammatory activation of macrophages. Furthermore, DADS ameliorated ethanol-induced decline of peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1 (CPT1), and phosphorylated AMP-activated protein kinase (AMPK) protein levels in mice liver and AML12 cells. These results demonstrate that DADS could prevent ethanol-induced liver steatosis and early inflammation by regulating the gut-liver axis and maintaining fatty acid catabolism.
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Affiliation(s)
- Shi-Xuan Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hong Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shuo Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong Province, 252059, China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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25
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Hu M, Chen Y, Deng F, Chang B, Luo J, Dong L, Lu X, Zhang Y, Chen Z, Zhou J. D-Mannose Regulates Hepatocyte Lipid Metabolism via PI3K/Akt/mTOR Signaling Pathway and Ameliorates Hepatic Steatosis in Alcoholic Liver Disease. Front Immunol 2022; 13:877650. [PMID: 35464439 PMCID: PMC9021718 DOI: 10.3389/fimmu.2022.877650] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/17/2022] [Indexed: 11/25/2022] Open
Abstract
This study investigated the protective properties and mechanisms of D-mannose against hepatic steatosis in experimental alcoholic liver disease (ALD). Drinking-water supplementation of D-mannose significantly attenuated hepatic steatosis in a standard mouse ALD model established by chronic-binge ethanol feeding, especially hepatocyte lipid deposition. This function of D-mannose on lipid accumulation in hepatocytes was also confirmed using ethanol-treated primary mouse hepatocytes (PMHs) with a D-mannose supplement. Meanwhile, D-mannose regulated lipid metabolism by rescuing ethanol-mediated reduction of fatty acid oxidation genes (PPARα, ACOX1, CPT1) and elevation of lipogenic genes (SREBP1c, ACC1, FASN). PI3K/Akt/mTOR signaling pathway was involved in this effect of D-mannose on lipid metabolism since PI3K/Akt/mTOR pathway inhibitors or agonists could abolish this effect in PMHs. Overall, our findings suggest that D-mannose exhibits its anti-steatosis effect in ALD by regulating hepatocyte lipid metabolism via PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Mengyao Hu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yu Chen
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Fan Deng
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Bo Chang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jialiang Luo
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Lijun Dong
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Xiao Lu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yi Zhang
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Zhengliang Chen
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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26
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Lee M, Nam SH, Yoon HG, Kim S, You Y, Choi KC, Lee YH, Lee J, Park J, Jun W. Fermented Curcuma longa L. Prevents Alcoholic Fatty Liver Disease in Mice by Regulating CYP2E1, SREBP-1c, and PPAR- α. J Med Food 2022; 25:456-463. [PMID: 35438556 DOI: 10.1089/jmf.2021.k.0098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We examined the efficacy of fermented Curcuma longa L. (FT) on the development of alcoholic fatty liver in mice and investigated the underlying mechanism. The protective potential of FT against ethanol-induced fatty liver was determined using C57BL/6 male mice allocated into four groups (8 mice/group). Control groups received either distilled water or 5 g/kg body weight (b.w.) per day ethanol for 8 days. Treatment groups were administered either 300 mg/kg b.w. per day of milk thistle or FT before receiving ethanol. FT contained a higher amount of caffeic acid and tetrahydrocurcumin than C. longa. FT pretreatment significantly suppressed the elevated hepatic lipid droplets associated with ethanol ingestion. In comparison with ethanol-treated control, FT pretreated mice showed inhibited cytochrome P4502E1 (CYP2E1), sterol regulatory element-binding protein-1 (SREBP-1c), and acetyl-CoA carboxylase production but elevated AMP-activated protein kinase, peroxisome proliferator-activated receptor-alpha (PPAR-α), and carnitine palmitoyltransferase 1 (CPT-1) levels. Taken together, FT is a promising hepatoprotectant for preventing of alcoholic fatty liver through modulating fatty acid synthesis and oxidation.
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Affiliation(s)
- Moeun Lee
- Division of Food and Nutrition, Chonnam National University, Gwangju, Korea.,Process Development and Fermentation Group, World Institute of Kimchi, Gwangju, Korea
| | - Seung-Hee Nam
- Institute of Agricultural Science and Technology, Chonnam National University, Gwangju, Korea
| | - Ho-Geun Yoon
- Department of Biochemistry and Molecular Biology, College of Medicine, Yonsei University, Seoul, Korea
| | - Shintae Kim
- Division of Food and Nutrition, Chonnam National University, Gwangju, Korea
| | - Yanghee You
- Division of Food and Nutrition, Chonnam National University, Gwangju, Korea
| | - Kyung-Chul Choi
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Yoo-Hyun Lee
- Department of Food and Nutrition, University of Suwon, Suwon, Korea
| | - Jeongmin Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
| | - Jeongjin Park
- Division of Food and Nutrition, Chonnam National University, Gwangju, Korea.,Research Institute for Human Ecology, Chonnam National University, Gwangju, Korea
| | - Woojin Jun
- Division of Food and Nutrition, Chonnam National University, Gwangju, Korea.,Research Institute for Human Ecology, Chonnam National University, Gwangju, Korea
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27
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Mihajlovic M, Vinken M. Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods. Int J Mol Sci 2022; 23:ijms23063315. [PMID: 35328737 PMCID: PMC8951158 DOI: 10.3390/ijms23063315] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
One of the major mechanisms of drug-induced liver injury includes mitochondrial perturbation and dysfunction. This is not a surprise, given that mitochondria are essential organelles in most cells, which are responsible for energy homeostasis and the regulation of cellular metabolism. Drug-induced mitochondrial dysfunction can be influenced by various factors and conditions, such as genetic predisposition, the presence of metabolic disorders and obesity, viral infections, as well as drugs. Despite the fact that many methods have been developed for studying mitochondrial function, there is still a need for advanced and integrative models and approaches more closely resembling liver physiology, which would take into account predisposing factors. This could reduce the costs of drug development by the early prediction of potential mitochondrial toxicity during pre-clinical tests and, especially, prevent serious complications observed in clinical settings.
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28
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Li T, Gong H, Zhan B, Mao X. Chitosan oligosaccharide attenuates hepatic steatosis in HepG2 cells via the activation of AMP‐activated protein kinase. J Food Biochem 2022; 46:e14045. [DOI: 10.1111/jfbc.14045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/25/2021] [Accepted: 11/24/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Tiange Li
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China Beijing China
| | - Han Gong
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China Beijing China
| | - Biyuan Zhan
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China Beijing China
| | - Xueying Mao
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China Beijing China
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29
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Gopal T, Ai W, Casey CA, Donohue TM, Saraswathi V. A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease. Alcohol Clin Exp Res 2021; 45:1927-1939. [PMID: 34558087 PMCID: PMC9153937 DOI: 10.1111/acer.14698] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.
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Affiliation(s)
- Thiyagarajan Gopal
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Weilun Ai
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Carol A. Casey
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Terrence M. Donohue
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Viswanathan Saraswathi
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
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30
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Birková A, Hubková B, Čižmárová B, Bolerázska B. Current View on the Mechanisms of Alcohol-Mediated Toxicity. Int J Mol Sci 2021; 22:9686. [PMID: 34575850 PMCID: PMC8472195 DOI: 10.3390/ijms22189686] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Alcohol is a psychoactive substance that is widely used and, unfortunately, often abused. In addition to acute effects such as intoxication, it may cause many chronic pathological conditions. Some of the effects are very well described and explained, but there are still gaps in the explanation of empirically co-founded dysfunction in many alcohol-related conditions. This work focuses on reviewing actual knowledge about the toxic effects of ethanol and its degradation products.
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Affiliation(s)
- Anna Birková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Hubková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Čižmárová
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Bolerázska
- 1st Department of Stomatology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
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31
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Monson EA, Trenerry AM, Laws JL, Mackenzie JM, Helbig KJ. Lipid droplets and lipid mediators in viral infection and immunity. FEMS Microbiol Rev 2021; 45:fuaa066. [PMID: 33512504 PMCID: PMC8371277 DOI: 10.1093/femsre/fuaa066] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/02/2020] [Indexed: 12/14/2022] Open
Abstract
Lipid droplets (LDs) contribute to key pathways important for the physiology and pathophysiology of cells. In a homeostatic view, LDs regulate the storage of neutral lipids, protein sequestration, removal of toxic lipids and cellular communication; however, recent advancements in the field show these organelles as essential for various cellular stress response mechanisms, including inflammation and immunity, with LDs acting as hubs that integrate metabolic and inflammatory processes. The accumulation of LDs has become a hallmark of infection, and is often thought to be virally driven; however, recent evidence is pointing to a role for the upregulation of LDs in the production of a successful immune response to viral infection. The fatty acids housed in LDs are also gaining interest due to the role that these lipid species play during viral infection, and their link to the synthesis of bioactive lipid mediators that have been found to have a very complex role in viral infection. This review explores the role of LDs and their subsequent lipid mediators during viral infections and poses a paradigm shift in thinking in the field, whereby LDs may play pivotal roles in protecting the host against viral infection.
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Affiliation(s)
- Ebony A Monson
- School of Life Sciences, La Trobe University, Melbourne, Australia, 3083
| | - Alice M Trenerry
- Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia, 3000
| | - Jay L Laws
- School of Life Sciences, La Trobe University, Melbourne, Australia, 3083
| | - Jason M Mackenzie
- Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia, 3000
| | - Karla J Helbig
- School of Life Sciences, La Trobe University, Melbourne, Australia, 3083
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32
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Yan J, Nie Y, Luo M, Chen Z, He B. Natural Compounds: A Potential Treatment for Alcoholic Liver Disease? Front Pharmacol 2021; 12:694475. [PMID: 34290612 PMCID: PMC8287649 DOI: 10.3389/fphar.2021.694475] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol intake is a direct cause of alcoholic liver disease (ALD). ALD usually manifests as fatty liver in the initial stage and then develops into alcoholic hepatitis (ASH), fibrosis and cirrhosis. Severe alcoholism induces extensive hepatocyte death, liver failure, and even hepatocellular carcinoma (HCC). Currently, there are few effective clinical means to treat ALD, except for abstinence. Natural compounds are a class of compounds extracted from herbs with an explicit chemical structure. Several natural compounds, such as silymarin, quercetin, hesperidin, and berberine, have been shown to have curative effects on ALD without side effects. In this review, we pay particular attention to natural compounds and developing clinical drugs based on natural compounds for ALD, with the aim of providing a potential treatment for ALD.
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Affiliation(s)
- Junbin Yan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yunmeng Nie
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Minmin Luo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhiyun Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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33
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Park S, Song J, Baek IJ, Jang KY, Han CY, Jun DW, Kim PK, Raught B, Jin EJ. Loss of Acot12 contributes to NAFLD independent of lipolysis of adipose tissue. Exp Mol Med 2021; 53:1159-1169. [PMID: 34285335 PMCID: PMC8333268 DOI: 10.1038/s12276-021-00648-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/11/2021] [Accepted: 06/03/2021] [Indexed: 12/20/2022] Open
Abstract
In this study, we hypothesized that deregulation in the maintenance of the pool of coenzyme A (CoA) may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Specific deletion of Acot12 (Acot12-/-), the major acyl-CoA thioesterase, induced the accumulation of acetyl-CoA and resulted in the stimulation of de novo lipogenesis (DNL) and cholesterol biosynthesis in the liver. KEGG pathway analysis suggested PPARα signaling as the most significantly enriched pathway in Acot12-/- livers. Surprisingly, the exposure of Acot12-/- hepatocytes to fenofibrate significantly increased the accumulation of acetyl-CoA and resulted in the stimulation of cholesterol biosynthesis and DNL. Interaction analysis, including proximity-dependent biotin identification (BioID) analysis, suggested that ACOT12 may directly interact with vacuolar protein sorting-associated protein 33A (VPS33A) and play a role in vesicle-mediated cholesterol trafficking and the process of lysosomal degradation of cholesterol in hepatocytes. In summary, in this study, we found that ACOT12 deficiency is responsible for the pathogenesis of NAFLD through the accumulation of acetyl-CoA and the stimulation of DNL and cholesterol via activation of PPARα and inhibition of cholesterol trafficking.
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Affiliation(s)
- Sujeong Park
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Jinsoo Song
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - In-Jeoung Baek
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Jeonbuk National University Medical School, Jeonju, Republic of Korea
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Chang Yeob Han
- School of Pharmacy, Jeonbuk National University, Jeonju, Jeonbuk, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Peter K Kim
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- Program of Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Brian Raught
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Eun-Jung Jin
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
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34
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Ratna A, Lim A, Li Z, Argemi J, Bataller R, Chiosis G, Mandrekar P. Myeloid Endoplasmic Reticulum Resident Chaperone GP96 Facilitates Inflammation and Steatosis in Alcohol-Associated Liver Disease. Hepatol Commun 2021; 5:1165-1182. [PMID: 34278167 PMCID: PMC8279472 DOI: 10.1002/hep4.1713] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/31/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022] Open
Abstract
Cellular stress-mediated chaperones are linked to liver macrophage activation and inflammation in alcohol-associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol-associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol-associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol-exposed macrophages. Myeloid-specific GP96 deficient (M-GP96KO) mice failed to induce alcohol-associated liver injury. Alcohol-fed M-GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro-inflammatory cytokines compared with wild-type mice. Anti-inflammatory cytokines interleukin-10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol-fed M-GP96KO livers. M-GP96KO mice exhibit protection in a model of endotoxin-mediated liver injury in vivo, which is in agreement with reduced inflammatory responses during ex vivo lipopolysaccharide/endotoxin- stimulated bone marrow-derived macrophages from M-GP96KO mice. Furthermore, we show that liver macrophages from alcohol-fed M-GP96KO mice show compensatory induction of GRP78 messenger RNA, likely due to increased splicing of X-box binding protein-1. Finally, we show that inhibition of GP96 using a specific pharmacological agent, PU-WS13 or small interfering RNA, alleviates inflammatory responses in primary macrophages. Conclusion: Myeloid ER resident GP96 promotes alcohol-induced liver damage through activation of liver macrophage inflammatory responses, alteration in lipid homeostasis, and ER stress. These findings highlight a critical role for liver macrophage ER resident chaperone GP96/HSP90B1 in ALD, and its targeted inhibition represents a promising therapeutic approach in ALD.
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Affiliation(s)
- Anuradha Ratna
- Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Arlene Lim
- Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Zihai Li
- Division of Medical OncologyDepartment of MedicinePelotonia Institute for Immuno‐OncologyThe Ohio State University Comprehensive Cancer CenterColumbusOHUSA
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and NutritionPittsburgh Liver Research CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and NutritionPittsburgh Liver Research CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Gabriela Chiosis
- Chemical Biology ProgramMemorial Sloan Kettering Cancer CenterNew YorkNYUSA
| | - Pranoti Mandrekar
- Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterMAUSA
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35
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Zhao L, Mehmood A, Yuan D, Usman M, Murtaza MA, Yaqoob S, Wang C. Protective Mechanism of Edible Food Plants against Alcoholic Liver Disease with Special Mention to Polyphenolic Compounds. Nutrients 2021; 13:nu13051612. [PMID: 34064981 PMCID: PMC8151346 DOI: 10.3390/nu13051612] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/06/2021] [Accepted: 05/08/2021] [Indexed: 12/13/2022] Open
Abstract
Alcoholic liver disease (ALD) is one type of liver disease, causing a global healthcare problem and mortality. The liver undergoes tissue damage by chronic alcohol consumption because it is the main site for metabolism of ethanol. Chronic alcohol exposure progresses from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which further lead to fibrosis, cirrhosis, and even hepatocellular cancer. Therapeutic interventions to combat ALD are very limited such as use of corticosteroids. However, these therapeutic drugs are not effective for long-term usage. Therefore, additional effective and safe therapies to cope with ALD are urgently needed. Previous studies confirmed that edible food plants and their bioactive compounds exert a protective effect against ALD. In this review article, we summarized the hepatoprotective potential of edible food plants and their bioactive compounds. The underlying mechanism for the prevention of ALD by edible food plants was as follows: anti-oxidation, anti-inflammation, lipid regulation, inhibition of apoptosis, gut microbiota composition modulation, and anti-fibrosis.
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Affiliation(s)
- Liang Zhao
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; (L.Z.); (A.M.); (M.U.); (C.W.)
- Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Arshad Mehmood
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; (L.Z.); (A.M.); (M.U.); (C.W.)
- Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Dongdong Yuan
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; (L.Z.); (A.M.); (M.U.); (C.W.)
- Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
- Correspondence: ; Tel.: +86-10-6898-4547
| | - Muhammad Usman
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; (L.Z.); (A.M.); (M.U.); (C.W.)
- Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Mian Anjum Murtaza
- Institute of Food Science and Nutrition, University of Sargodha, Sargodha 40100, Pakistan;
| | - Sanabil Yaqoob
- Department of Food Science and Technology, University of Central Punjab, Punjab 54590, Pakistan;
| | - Chengtao Wang
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; (L.Z.); (A.M.); (M.U.); (C.W.)
- Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
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Skinner RC, Hagaman JA. The interplay of Western diet and binge drinking on the onset, progression, and outlook of liver disease. Nutr Rev 2021; 80:503-512. [PMID: 33969426 DOI: 10.1093/nutrit/nuab031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease and alcoholic liver disease, the two most prevalent liver diseases worldwide, share a common pathology but have largely been considered disparate diseases. Liver diseases are widely underestimated, but their prevalence is increasing worldwide. The Western diet (high-fat, high-sugar) and binge drinking (rapid consumption of alcohol in a short period of time) are two highly prevalent features of standard life in the United States, and both are linked to the development and progression of liver disease. Yet, few studies have been conducted to elucidate their potential interactions. Data shows binge drinking is on the rise in several age groups, and poor dietary trends continue to be prevalent. This review serves to summarize the sparse findings on the hepatic consequences of the combination of binge drinking and consuming a Western diet, while also drawing conclusions on potential future impacts. The data suggest the potential for a looming liver disease epidemic, indicating that more research on its progression as well as its prevention is needed on this critical topic.
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Affiliation(s)
- R Chris Skinner
- R. C. Skinner and J. A. Hagaman are with the Division of Natural Sciences and Mathematics, University of the Ozarks, Clarksville, Arkansas, USA
| | - Joel A Hagaman
- R. C. Skinner and J. A. Hagaman are with the Division of Natural Sciences and Mathematics, University of the Ozarks, Clarksville, Arkansas, USA
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The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease. LIVERS 2021. [DOI: 10.3390/livers1020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. Both are on the increase globally and, apart from liver transplantation, there are no licensed therapies that target the full complement of disease features. The presence of some shared pathogenic mechanisms and histological features in NAFLD and ALD suggests that it may be possible to develop markers for prognostication or staging, or indeed new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome results in hepatocyte pyroptosis, persistence, and amplification of liver inflammation and activation of profibrogenic signaling cascades. Thus, targeting elements of the pathway in NAFLD and ALD may provide a tractable route to pharmacological therapy. In this review, we summarize the contribution of this inflammasome to disease and review the current options for therapy.
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Assessment of the association between body composition and risk of non-alcoholic fatty liver. PLoS One 2021; 16:e0249223. [PMID: 33793621 PMCID: PMC8016222 DOI: 10.1371/journal.pone.0249223] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/12/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as the condition of fat accumulation in the liver. This cross-sectional study aimed to investigate the relationship between body composition and fatty liver and determine of cut-off point for predicting NAFLD. Samples were selected from the nutrition clinic from 2016 to 2017 in Tehran, Iran. The liver steatosis was calculated using the CAP score through the FiroScan™ and body composition was measured using the dual-energy X-ray absorptiometry scan method. A total of 2160 patients participated in this study, 745 (34.5%) subjects had NAFLD. We found that fat-free tissue was inversely and fat tissue was directly correlated with the risk of NAFLD in almost all factors and the risk of developing NAFLD increases if the total fat exceeds 32.23% and 26.73% in women and men and abdominal fat exceeds 21.42% and 13.76% in women and men, respectively. Finally, we realized that the total fat percent had the highest AUC (0.932 for men and 0.917 for women) to predict the risk of NAFLD. Overall, the likelihood of NAFLD development rose significantly with increasing the amount of total fat and abdominal fat from the cut-off point level.
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Bianco C, Casirati E, Malvestiti F, Valenti L. Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets. JHEP Rep 2021; 3:100284. [PMID: 34027340 PMCID: PMC8122117 DOI: 10.1016/j.jhepr.2021.100284] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well.
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Key Words
- AA, arachidonic acid
- ASH, alcoholic steatohepatitis
- DAG, diacylglycerol
- DNL, de novo lipogenesis
- ER, endoplasmic reticulum
- FFAs, free fatty acids
- FGF19, fibroblast growth factor 19
- FLD, fatty liver disease
- FXR, farnesoid X receptor
- GCKR, glucokinase regulator
- GPR55, G protein-coupled receptor 55
- HCC, hepatocellular carcinoma
- HFE, homeostatic iron regulator
- HSC, hepatic stellate cells
- HSD17B13, hydroxysteroid 17-beta dehydrogenase 13
- IL-, interleukin-
- IL32
- LDs, lipid droplets
- LPI, lysophosphatidyl-inositol
- MARC1, mitochondrial amidoxime reducing component 1
- MBOAT7
- MBOAT7, membrane bound O-acyltransferase domain-containing 7
- NASH, non-alcoholic steatohepatitis
- PNPLA3
- PNPLA3, patatin like phospholipase domain containing 3
- PPAR, peroxisome proliferator-activated receptor
- PRS, polygenic risk score
- PUFAs, polyunsaturated fatty acids
- SREBP, sterol response element binding protein
- TAG, triacylglycerol
- TNF-α, tumour necrosis factor-α
- alcoholic liver disease
- cirrhosis
- fatty liver disease
- genetics
- interleukin-32
- non-alcoholic fatty liver disease
- precision medicine
- steatohepatitis
- therapy
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Affiliation(s)
- Cristiana Bianco
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elia Casirati
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Francesco Malvestiti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Luca Valenti
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Zhang Y, Bi M, Chen Z, Dai M, Zhou G, Hu Y, Yang H, Guan W. Hydrogen gas alleviates acute alcohol-induced liver injury by inhibiting JNK activation. Exp Ther Med 2021; 21:453. [PMID: 33767761 PMCID: PMC7976433 DOI: 10.3892/etm.2021.9884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 12/08/2020] [Indexed: 11/09/2022] Open
Abstract
Binge alcohol drinking is fast becoming a global health concern, with the liver among the first organ involved and the one afflicted with the greatest degree of injury. Oxidative stress, alterations in hepatic metabolism, immunity and inflammation have all been reported to contribute to the development of alcoholic liver disease (ALD). Hydrogen gas (H2) serves a key role in the modulation of hepatic redox, immune and inflammatory homeostasis. However, the effects of treatment using intraperitoneal injection of H2 on ALD remain unexplored. Therefore, the aim of the present study was to investigate the effects and underlying mechanism of intraperitoneal injection of H2 on acute alcohol-induced liver injury in a mouse model. H2 was administered by daily intraperitoneal injections (1.0 ml/100 g) for 4 days. On day 4, the mice received H2 after fasting for 5.5 h. After 30 min, the mice were administered with 33% (v/v) ethanol at a cumulative dose of 4.5 g/kg body weight by four equally divided gavages at 20-min intervals. Blood and liver tissues were collected at 16 h after the first ethanol gavage. Subsequently, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride and total cholesterol (TC) levels were analyzed using an Automatic Clinical Analyzer. Hepatic JNK activity and GAPDH levels were examined by western blotting. It was observed that acute ethanol gavage induced liver injury, as indicated by significantly increased serum ALT and AST levels, which were effectively decreased by H2 at 16 h after the first ethanol gavage. In addition, H2 treatment reduced serum TC levels in the Alcohol+H2 group when compared with those in Alcohol group. Mechanistically, H2 attenuated hepatic JNK phosphorylation induced by acute ethanol gavage. Therefore, the results of the present study demonstrated that treatment with exogenous H2 by intraperitoneal injection may alleviate acute alcohol-induced liver injury by inhibiting hepatic JNK activation, which may represent a novel therapeutic strategy for ALD.
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Affiliation(s)
- Yaxing Zhang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Mingmin Bi
- Department of Otorhinolaryngology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518107, P.R. China.,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zifeng Chen
- Biofeedback Laboratory, Xinhua College of Sun Yat-sen University, Guangzhou, Guangdong 510520, P.R. China.,Department of Biomedical Engineering, Xinhua College of Sun Yat-sen University, Guangzhou, Guangdong 510520, P.R. China
| | - Min Dai
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ge Zhou
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yuxuan Hu
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Hongzhi Yang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Weibing Guan
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
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Grander C, Schaefer B, Schwärzler J, Grabherr F, de Graaf DM, Enrich B, Oberhuber G, Mayr L, Sangineto M, Jaschke N, Adolph TE, Effenberger M, Moschen AR, Dinarello CA, Zoller H, Tilg H. Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans. Gut 2021; 70:585-594. [PMID: 32699098 DOI: 10.1136/gutjnl-2020-321375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.
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Affiliation(s)
- Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Benedikt Schaefer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Dennis M de Graaf
- Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
| | - Barbara Enrich
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Institute of Pathology, University Hospital of Innsbruck, Innsbruck, Austria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Moris Sangineto
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Nikolai Jaschke
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander R Moschen
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Charles A Dinarello
- Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
| | - Heinz Zoller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
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42
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Sheriff L, Khan RS, Saborano R, Wilkin R, Luu NT, Gunther UL, Hubscher SG, Newsome PN, Lalor PF. Alcoholic hepatitis and metabolic disturbance in female mice: a more tractable model than Nrf2-/- animals. Dis Model Mech 2020; 13:dmm046383. [PMID: 33067186 PMCID: PMC7790192 DOI: 10.1242/dmm.046383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022] Open
Abstract
Alcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 15% mortality rate within 28 days in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of ad libitum delivery of alcohol but without any additional insult, and is associated with relatively mild liver injury. The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) protects against oxidative stress, and mice deficient in this molecule are suggested to be more sensitive to alcohol-induced injury. We have established a novel model of AH in mice and compared the nature of liver injury in C57/BL6 wild-type (WT) versus Nrf2-/- mice. Our data showed that both WT and Nrf2-/- mice demonstrate robust weight loss, and an increase in serum transaminase, steatosis and hepatic inflammation when exposed to diet and ethanol. This is accompanied by an increase in peripheral blood and hepatic myeloid cell populations, fibrogenic response and compensatory hepatocyte regeneration. We also noted characteristic disturbances in hepatic carbohydrate and lipid metabolism. Importantly, use of Nrf2-/- mice did not increase hepatic injury responses in our hands, and female WT mice exhibited a more-reproducible response. Thus, we have demonstrated that this simple murine model of AH can be used to induce an injury that recreates many of the key human features of AH - without the need for challenging surgical procedures to administer ethanol. This will be valuable for understanding of the pathogenesis of AH, for testing new therapeutic treatments or devising metabolic approaches to manage patients whilst in medical care.This article has an associated First Person interview with the joint first authors of the paper.
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Affiliation(s)
- Lozan Sheriff
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Reenam S Khan
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Raquel Saborano
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Richard Wilkin
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Nguyet-Thin Luu
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ulrich L Gunther
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK
- Institute of Chemistry and Metabolomics, University of Lübeck, 23562 Lübeck, Germany
| | - Stefan G Hubscher
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Liver Unit, University Hospitals Birmingham, Birmingham B15 2TH, UK
- Department of Cellular Pathology, University Hospitals Birmingham, Birmingham B15 2TH, UK
| | - Philip N Newsome
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Patricia F Lalor
- Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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Lamas-Paz A, Morán L, Peng J, Salinas B, López-Alcántara N, Sydor S, Vilchez-Vargas R, Asensio I, Hao F, Zheng K, Martín-Adrados B, Moreno L, Cogolludo A, Gómez del Moral M, Bechmann L, Martínez-Naves E, Vaquero J, Bañares R, Nevzorova YA, Cubero FJ. Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury. Front Pharmacol 2020; 11:603771. [PMID: 33408632 PMCID: PMC7779758 DOI: 10.3389/fphar.2020.603771] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022] Open
Abstract
Binge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0-100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota-increased Lactobacillus and decreased Lachnospiraceae species-were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1β), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapy.
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Affiliation(s)
- Arantza Lamas-Paz
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
| | - Laura Morán
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Jin Peng
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Beatriz Salinas
- Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
- Bioengineering and Aerospace Engineering Department, Universidad Carlos III de Madrid, Madrid, Spain
- Centro de Investigación Biomédico en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Nuria López-Alcántara
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - Svenja Sydor
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Ramiro Vilchez-Vargas
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
| | - Iris Asensio
- Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Fengjie Hao
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
- Department of General Surgery, Hepatobiliary Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kang Zheng
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
- Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Beatriz Martín-Adrados
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
| | - Laura Moreno
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
- Department of Pharmacology and Toxicology, Complutense University School of Medicine and Centre for Biomedical Research, Network on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Angel Cogolludo
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
- Department of Pharmacology and Toxicology, Complutense University School of Medicine and Centre for Biomedical Research, Network on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Manuel Gómez del Moral
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
- Department of Cell Biology, Complutense University School of Medicine, Madrid, Spain
| | - Lars Bechmann
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Eduardo Martínez-Naves
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
| | - Javier Vaquero
- Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Rafael Bañares
- Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
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Raikhelson KL, Kondrashina EA, Pazenko EV. [Mixed steatohepatitis: more questions than answers (Part 1)]. TERAPEVT ARKH 2020; 92:91-96. [PMID: 33720580 DOI: 10.26442/00403660.2020.12.200470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 02/07/2021] [Indexed: 12/12/2022]
Abstract
The term steatohepatitis is used for a heterogeneous group of diseases of various etiologies, characterized by a similar morphological picture. Earlier the diagnosis of non-alcoholic fatty liver disease implied the exclusion of other causes of steatohepatitis, in recent years it has been suggested that a combination of various etiological variants of steatohepatitis is possible. The review considers the terminological, epidemiological and pathogenetic aspects of the most common combination: metabolic and alcoholic genesis, the issues of the mutual influence of etiopathogenetic factors and the identification of the predominant process. Issues of existing and prospective pathogenetic and symptomatic therapy are discussed in detail. Treatment of steatohepatitis is based on the elimination of known causal factors and lifestyle modification; therapy includes medications, that have been proven to be effective in certain types of steatohepatitis and symptomatic therapy as well.
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Affiliation(s)
- K L Raikhelson
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University
| | - E A Kondrashina
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University
| | - E V Pazenko
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University
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Microbiota reprogramming for treatment of alcohol-related liver disease. Transl Res 2020; 226:26-38. [PMID: 32687975 PMCID: PMC7572584 DOI: 10.1016/j.trsl.2020.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/01/2020] [Accepted: 07/13/2020] [Indexed: 02/08/2023]
Abstract
In the past decade knowledge has expanded regarding the importance of the gut microbiota in maintaining intestinal homeostasis and overall health. During this same time, we have also gained appreciation for the role of the gut-liver axis in the development of liver diseases. Alcohol overconsumption is one of the leading causes of liver failure globally. However, not all people with alcohol use disorder progress to advanced stages of liver disease. With advances in technology to investigate the gut microbiome and metabolome, we are now beginning to delineate alcohol's effects on the gut microbiome in relation to liver disease. This review presents our current understanding on the role of the gut microbiota during alcohol exposure, and various therapeutic attempts that have been made to reprogram the gut microbiota with the goal of alleviating alcoholic-related liver disease.
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Ren R, Wang Z, Wu M, Wang H. Emerging Roles of SIRT1 in Alcoholic Liver Disease. Int J Biol Sci 2020; 16:3174-3183. [PMID: 33162823 PMCID: PMC7645991 DOI: 10.7150/ijbs.49535] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide with a wide spectrum of liver pathologies ranging from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. It has been demonstrated that ALD is mediated in whole or in part by a central signaling molecule sirtuin 1 (SIRT1), a conserved class III histone deacetylase.SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, inhibiting hepatic inflammation, controlling hepatic fibrosis and mediating hepatocellular carcinoma in ALD. However, underlying molecular mechanisms are complex and remain incompletely understood. The aim of this review was to highlight the latest advances in understanding of SIRT1 regulatory mechanisms in ALD and discuss their unique potential role as novel therapeutic target for ALD treatment.
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Affiliation(s)
- Ruixue Ren
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Ziming Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Miaomiao Wu
- School of Pharmacy, Institute of Liver Diseases, Anhui Medical University, Hefei 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.,School of Pharmacy, Institute of Liver Diseases, Anhui Medical University, Hefei 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, Anhui, China
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Dong R, Wang X, Wang L, Wang C, Huang K, Fu T, Liu K, Wu J, Sun H, Meng Q. Yangonin inhibits ethanol-induced hepatocyte senescence via miR-194/FXR axis. Eur J Pharmacol 2020; 890:173653. [PMID: 33068587 DOI: 10.1016/j.ejphar.2020.173653] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
Chronic alcohol assumption has been recognized as a major cause of alcoholic liver disease (ALD), which ranges from alcoholic steatohepatitis to fibrosis and hepatocellular carcinoma. Alcoholic liver disease has become the leading cause of liver-related health problem in the world. Herewith, effective therapeutic strategy for alcoholic liver disease is necessary. Yangonin (Yan), a bioactive compound extract from Kava, has been reported to exert hepatoprotective effects via Farnesoid X receptor (FXR) activation. The present study aims to investigate whether Yan ameliorated the ethanol-stimulated liver injury and further to elucidate the mechanisms in vivo and in vitro. Yan improved cell viabilities via cell count kit-8 (CCK-8) methods and obviously reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG) levels. We detected miR-194 levels in ethanol-induced LO2 cells and male C57BL/6 mice by quantitative real-time PCR. Also, the effects of miR-194 on modulating cellular senescence via targeting FXR were further verified. The cellular senescence markers p16, p21, telomerase activity and senescence-related β-galactosidase (SA-β-gal) were evaluated by quantitative real-time PCR and Western blot. Also, LO2 cells or liver tissues were stained with special primary antibodies and 4',6'-Diamidino-2-phenylindole (DAPI). The cell cycle was detected by flow cytometry. We observed that Yan significantly inhibited ethanol-induced cellular senescence via FXR activation (P < 0.05). Our results demonstrate that Yan significantly reduced the cellular markers p16, p21 and Hmga1 expression and inhibited the cell cycle arrest (P < 0.05). MiR-194 was upregulated in the alcoholic liver disease, which was significantly suppressed by Yan (P < 0.05). Moreover, miR-194 mimic inhibited FXR expression in vitro. In summary, these aggregated data demonstrate that Yan alleviates chronic ethanol-induced liver injury through inhibition of cellular senescence via regulating miR-194/FXR axis.
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Affiliation(s)
- Renchao Dong
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Xiaohui Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Lu Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Changyuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Kai Huang
- Drug Clinical Trial Institution, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Ting Fu
- Pharmacy Department of Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Kexin Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Jingjing Wu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Huijun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
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Robinson KE, Shah VH. Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:49. [PMID: 33073044 DOI: 10.21037/tgh.2019.12.05] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) account for the majority of hepatic morbidity and deaths due to cirrhosis in the United States. ALD is an umbrella term for a number of conditions linked to excessive alcohol consumption including simple steatosis, cirrhosis, acute alcoholic hepatitis (AH) with or without cirrhosis, and hepatocellular carcinoma (HCC) as a complication of cirrhosis. Although it presents with histological features resembling alcohol-induced liver injury, NAFLD occurs in patients with little or no history of alcohol consumption. NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. The pathogenesis is not fully understood for either disease. Development of severe liver disease is highly variable amongst chronic abusers of alcohol. Sex, age, genetics, host microbiome, and behavior are all factors linked to the development of ALD. These factors also contribute to NAFLD, but by contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role.
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Affiliation(s)
- Kyle E Robinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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49
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Harnessing the Proteostasis Network in Alcohol-associated Liver Disease. CURRENT PATHOBIOLOGY REPORTS 2020. [DOI: 10.1007/s40139-020-00211-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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50
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Arab JP, Cabrera D, Sehrawat TS, Jalan-Sakrikar N, Verma VK, Simonetto D, Cao S, Yaqoob U, Leon J, Freire M, Vargas JI, De Assuncao TM, Kwon JH, Guo Y, Kostallari E, Cai Q, Kisseleva T, Oh Y, Arrese M, Huebert RC, Shah VH. Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. J Hepatol 2020; 73:149-160. [PMID: 32087348 PMCID: PMC7305991 DOI: 10.1016/j.jhep.2020.02.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 01/23/2020] [Accepted: 02/01/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. METHODS Mice with HSC-selective deletion of NRP (ColCre/Nrp1loxP) or synectin (ColCre/synectinloxP) vs. paired Nrp1loxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. RESULTS ColCre/Nrp1loxP mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from ColCre/Nrp1loxP mice compared to supernatant from Nrp1loxP mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. CONCLUSION Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. LAY SUMMARY Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage.
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Affiliation(s)
- Juan P Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Daniel Cabrera
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile; Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vikas K Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Douglas Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Usman Yaqoob
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan Leon
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Mariela Freire
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Jose I Vargas
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | | | - Jung H Kwon
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yi Guo
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Qing Cai
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California-San Diego, San Diego, CA, USA
| | - Youngman Oh
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Marco Arrese
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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