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1
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Hu MX, Li JQ, Zhang HW, Ma YK, Zhao BJ, Xiao L, Liang W, Wang Y, Wang C, Wu CG, Liu TT. 1-benzyl-6-nitro-4-phenyl-4-(methoxycarbonyl)-2(1H)-pyridinone, a novel pirfenidone derivative, alleviate hepatic fibrosis through T cells. Biomed Pharmacother 2025; 184:117907. [PMID: 39978030 DOI: 10.1016/j.biopha.2025.117907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/17/2025] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
Hepatic fibrosis (HF) is a pathological process in many liver diseases, which lack of specific agents. Pirfenidone (PFD) derivatives are potential new drug. The purpose of this study was to investigate the effect and immunological mechanism of PFD derivatives on HF. A total of 11 PFD derivatives were designed, synthesized and screened. 1-benzyl-6-nitro-4-phenyl-4-(methoxycarbonyl)-2(1 H)-pyridinone (code: Compound 5) had optimal effect on inhibiting nitric oxide release, hepatic stellate cells (HSCs) and T cell proliferation, which suggested that Compound 5 showed anti-inflammatory, anti-fibrosis and immunoregulation effects. Compound 5 inhibited the proliferation of HSC-T6 and T cell in dose-dependent manner, the IC50 was 10.19 μM and 17.16 μM, respectively. Compound 5 inhibited the differentiation of CD8+T cells and promoted the differentiation of Tregs in the splenic T lymphocyte of CCl4-induced mouse HF model. Besides, Compound 5 promoted HSC-T6 apoptosis in dose-dependent manner, accompanied by the down-regulation of α-smooth muscle actin (α-SMA) and collagen-I (Col-I). In terms of mechanism, Compound 5 had no significant effect on glucose uptake of T cells. But it inhibited non-esterified fatty acid (NEFA) secretion of T cell by inhibiting the phosphorylation of PI3K-AKT-mTOR signal, which related to the metabolism of T cell. Subsequently, Compound 5 affected α-SMA and Col-I expression of HSC-T6 by T cell modulating in cell co-culture. CONCLUSION: Compound 5 is a promising new drug against HF by the dual role of inhibiting HSCs and modulating T cells lipid metabolism, which affects the immune microenvironment of HF.
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Affiliation(s)
- Meng-Xue Hu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Jia-Qi Li
- School of Pharmacy, South-Central Minzu University, Wuhan, China
| | - Hong-Wei Zhang
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Yu-Kun Ma
- Department of Pharmacy, the 902nd Hospital of the PLA Joint Logistics Support Force, Bengbu, China
| | - Bao-Jing Zhao
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Xiao
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Wei Liang
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Yamin Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, the Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Cheng-Gui Wu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.
| | - Ting-Ting Liu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China.
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2
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Duan F, Wu J, Chang J, Peng H, Liu Z, Liu P, Han X, Sun T, Shang D, Yang Y, Li Z, Li P, Liu Y, Zhu Y, Lv Y, Guo X, Zhao Y, An Y. Deciphering endocrine function of adipose tissue and its significant influences in obesity-related diseases caused by its dysfunction. Differentiation 2025; 141:100832. [PMID: 39709882 DOI: 10.1016/j.diff.2024.100832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
Current research has found that adipose tissue is not only involved in energy metabolism, but also a highly active endocrine organ that secretes various adipokines, including adiponectin, leptin, resistin and apelin, which are involved in the regulation of physiology and pathology of tissues and organs throughout the body. With the yearly increasing incidence, obesity has become a risk factor for a variety of pathological changes, including inflammation and metabolic syndrome in various system (endocrine, circulatory, locomotor and central nervous system). Thus these symptoms lead to multi-organ dysfunctions, including the heart, liver, kidneys, brain and joints. An in-depth summary of the roles of adipokines in the regulation of other tissues and organs can help to provide more effective therapeutic strategies for obesity-related diseases and explore potential therapeutic targets. Therefore, this review has retrospected the endocrine function of adipose tissue under obesity and the role of dysregulated adipokine secretion in related diseases and the underlying mechanisms, in order to provide a theoretical basis for targeting adipokine-mediated systemic dysregulation.
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Affiliation(s)
- Feiyi Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiaoyan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiayi Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Haoyuan Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zitao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengfei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Dandan Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yutian Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengkun Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yixuan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yonghao Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Yunzhi Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Xiumei Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Ying Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China.
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Chen T, Yang W, Dong R, Yao H, Sun M, Wang J, Zhou Q, Xu J. The effect and application of adiponectin in hepatic fibrosis. Gastroenterol Rep (Oxf) 2024; 12:goae108. [PMID: 39737222 PMCID: PMC11683834 DOI: 10.1093/gastro/goae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 01/01/2025] Open
Abstract
Hepatic fibrosis, a degenerative liver lesion, significantly contributes to the deterioration and mortality among patients with chronic liver diseases. The condition arises from various factors including toxins, such as alcohol, infections like different types of viral hepatitis, and metabolic diseases. Currently, there are no effective treatments available for liver fibrosis. Recent research has shown that adiponectin (ADPN) exhibits inhibitory effects on hepatic fibrosis. ADPN, an adipocytokine secreted by mature adipocytes, features receptors that are widely distributed across multiple tissues, especially the liver. In the liver, direct effects of ADPN on liver fibrosis include reducing inflammation and regulating hepatic stellate cell proliferation and migration. And its indirect effects include alleviating hepatic endoplasmic reticulum stress and reducing inflammation in hepatic lobules, thereby mitigating hepatic fibrosis. This review aims to elucidate the regulatory role of ADPN in liver fibrosis, explore how ADPN and its receptors alleviate endoplasmic reticulum stress, summarize ADPN detection methods, and discuss its potential as a novel marker and therapeutic agent in combating hepatic fibrosis.
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Affiliation(s)
- Taoran Chen
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Wenjing Yang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Rongrong Dong
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Han Yao
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Miao Sun
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiaxin Wang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Qi Zhou
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiancheng Xu
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
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4
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Tao J, Li H, Wang H, Tan J, Yang X. Metabolic dysfunction-associated fatty liver disease and osteoporosis: the mechanisms and roles of adiposity. Osteoporos Int 2024; 35:2087-2098. [PMID: 39136721 DOI: 10.1007/s00198-024-07217-y] [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: 03/13/2024] [Accepted: 07/26/2024] [Indexed: 11/21/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has recently been renamed metabolic dysfunction-associated fatty liver disease (MAFLD) by international consensus. Both MAFLD and osteoporosis are highly prevalent metabolic diseases. Recent evidence indicates that NAFLD increases the risk of low bone mineral density and osteoporosis, likely mediated by obesity. NAFLD has a close association with obesity and other metabolic disorders. Although obesity was previously thought to protect against bone loss, it now heightens osteoporotic fracture risk. This overview summarizes current clinical correlations between obesity, NAFLD, and osteoporosis, with a focus on recent insights into potential mechanisms interconnecting these three conditions. This study reviewed the scientific literature on the relationship between obesity, nonalcoholic fatty liver disease, and osteoporosis as well as the scientific literature that reveals the underlying pathophysiologic mechanisms between the three. Emerging evidence suggests obesity plays a key role in mediating the relationship between NAFLD and osteoporosis. Accumulating laboratory evidence supports plausible pathophysiological links between obesity, NAFLD, and osteoporosis, including inflammatory pathways, insulin resistance, gut microbiota dysbiosis, bone marrow adiposity, and alterations in insulin-like growth factor-1 signaling. Adiposity has important associations with NAFLD and osteoporosis, the underlying pathophysiologic mechanisms between the three may provide new therapeutic targets for this complex patient population.
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Affiliation(s)
- Jie Tao
- Department of General Practice, the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China
| | - Hong Li
- Department of Health Management Center, the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China
| | - Honggang Wang
- Department of Gastroenterology, the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China
| | - Juan Tan
- Department of General Practice, the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China.
| | - Xiaozhong Yang
- Department of Gastroenterology, the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China.
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Wu J, Wen L, Liu X, Li Q, Sun Z, Liang C, Xie F, Li X. Silybin: A Review of Its Targeted and Novel Agents for Treating Liver Diseases Based on Pathogenesis. Phytother Res 2024; 38:5713-5740. [PMID: 39310970 DOI: 10.1002/ptr.8347] [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: 06/18/2024] [Revised: 09/02/2024] [Accepted: 09/09/2024] [Indexed: 12/13/2024]
Abstract
Liver disease represents a significant global public health concern. Silybin, derived from Silybum marianum, has been demonstrated to exhibit a range of beneficial properties, including anti-inflammatory, antioxidative, antifibrotic, antiviral, and cytoprotective effects. These attributes render it a promising candidate for the treatment of liver fibrosis, cirrhosis, liver cancer, viral hepatitis, non-alcoholic fatty liver disease, and other liver conditions. Nevertheless, its low solubility and low bioavailability have emerged as significant limitations in its clinical application. To address these limitations, researchers have developed a number of silybin formulations. This study presents a comprehensive review of the results of research on silybin for the treatment of liver diseases in recent decades, with a particular focus on novel formulations based on the pathogenesis of the disease. These include approaches targeting the liver via the CD44 receptor, folic acid, vitamin A, and others. Furthermore, the study presents the findings of studies that have employed nanotechnology to enhance the low bioavailability and low solubility of silybin. This includes the use of nanoparticles, liposomes, and nanosuspensions. This study reviews the application of silybin preparations in the treatment of global liver diseases. However, further high-quality and more complete experimental studies are still required to gain a more comprehensive understanding of the efficacy and safety of these preparations. Finally, the study considers the issues that arise during the research of silybin formulations.
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Affiliation(s)
- Jijiao Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin Wen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zihao Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuipeng Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Liu X, Liang Q, Wang Y, Xiong S, Yue R. Advances in the pharmacological mechanisms of berberine in the treatment of fibrosis. Front Pharmacol 2024; 15:1455058. [PMID: 39372209 PMCID: PMC11450235 DOI: 10.3389/fphar.2024.1455058] [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: 06/26/2024] [Accepted: 09/09/2024] [Indexed: 10/08/2024] Open
Abstract
The rising incidence of fibrosis poses a major threat to global public health, and the continuous exploration of natural products for the effective treatment of fibrotic diseases is crucial. Berberine (BBR), an isoquinoline alkaloid, is widely used clinically for its anti-inflammatory, anti-tumor and anti-fibrotic pharmacological effects. Until now, researchers have worked to explore the mechanisms of BBR for the treatment of fibrosis, and multiple studies have found that BBR attenuates fibrosis through different pathways such as TGF-β/Smad, AMPK, Nrf2, PPAR-γ, NF-κB, and Notch/snail axis. This review describes the anti-fibrotic mechanism of BBR and its derivatives, and the safety evaluation and toxicity studies of BBR. This provides important therapeutic clues and strategies for exploring new drugs for the treatment of fibrosis. Nevertheless, more studies, especially clinical studies, are still needed. We believe that with the continuous implementation of high-quality studies, significant progress will be made in the treatment of fibrosis.
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Affiliation(s)
- Xiaoqin Liu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qingzhi Liang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | | | - Shuai Xiong
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Rensong Yue
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Egresi A, Blázovics A, Lengyel G, Tóth AG, Csongrády B, Jakab Z, Hagymási K. Redox Homeostasis and Non-Invasive Assessment of Significant Liver Fibrosis by Shear Wave Elastography. Diagnostics (Basel) 2024; 14:1945. [PMID: 39272729 PMCID: PMC11394606 DOI: 10.3390/diagnostics14171945] [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: 06/18/2024] [Revised: 08/15/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatic fibrosis with various origins can be estimated non-invasively by using certain biomarkers and imaging-based measurements. The aim of our study was to examine redox homeostasis biomarkers and liver stiffness measurements for the assessment of significant liver fibrosis in different etiologies of chronic liver diseases. A cohort study consisting of 88 chronic liver disease patients of both sexes (age 49.1 ± 14.7 years) was performed. Cytokine profiles as well as redox homeostasis characteristics were determined. Liver fibrosis stages were assessed with shear wave elastography. The plasma levels of four cytokines showed no significant alteration between the four fibrotic stages; however, higher values were measured in the F2-4 stages. Free sulfhydryl group concentration, the marker of redox homeostasis, was lower in significant fibrosis (F0-F1: 0.36 ± 0.06 vs. F2-4: 0.29 ± 0.08 mmol/L, p < 0.05). Higher chemiluminescence values, as free radical-antioxidant parameters, were detected in advanced fibrosis stages in erythrocytes (F0-F1: 36.00 ± 37.13 vs. F2-4: 51.47 ± 44.34 RLU%). These data suggest that oxidative stress markers can predict significant fibrosis, with the aim of reducing the number of protocol liver biopsies in patients unlikely to have significant disease; however, their role in distinguishing between the certain fibrosis groups needs further studies.
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Affiliation(s)
- Anna Egresi
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1091 Budapest, Hungary
| | - Anna Blázovics
- Department of Surgical Research and Techniques, The Heart and Vascular Center, Semmelweis University, 1091 Budapest, Hungary
| | - Gabriella Lengyel
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1091 Budapest, Hungary
| | - Adrienn Gréta Tóth
- Centre for Bioinformatics, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Barbara Csongrády
- Department of Radiology, Semmelweis University, 1091 Budapest, Hungary
| | - Zsuzsanna Jakab
- Department of Internal Medicine and Oncology, Semmelweis University, 1091 Budapest, Hungary
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Wang CW, Huang CF, Yeh ML, Chen SC, Hung CH, Kuo CH, Huang JF, Dai CY, Chuang WL, Lung-Yu M. Hepatitis C virus infection associated with coronary and thoracic aortic atherosclerosis. Am J Med Sci 2024; 368:203-213. [PMID: 38368945 DOI: 10.1016/j.amjms.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 01/30/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND Coronary and thoracic aortic calcification was associated with stroke, coronary heart, and peripheral vascular disease. Hepatitis C virus (HCV) infection is significantly associated with insulin resistance, diabetes mellitus and hepatic steatosis. We aimed to investigate the relationship between HCV infection and coronary, thoracic aortic atherosclerosis. MATERIALS AND METHODS Calcification was detected by chest computed tomography and defined as any Agatston score greater than zero. Metabolic syndrome was based on the modified Adult Treatment Panel III criteria. Fibrosis-4 (FIB-4) and AST-to-platelet ratio (APRI) was calculated. The anti-HCV signal-to-cutoff (S/CO) ratio was determined by the third generation ELISA kit. Atherosclerosis risk was estimated by using multiple logistic regression modeling. RESULTS Being positive for both metabolic syndrome and HCV infection (OR = 2.65, 95% CI: 1.26-5.59, p = 0.007), negative for metabolic syndrome and positive for HCV infection (OR = 2.75, 95% CI: 1.48-5.30, p = 0.001), and positive for metabolic syndrome and negative for HCV infection (OR = 2.42, 95% CI: 1.92-3.07, p < 0.001) were associated with atherosclerosis compared with being negative for both metabolic syndrome and HCV infection (Ptrend< 0.001). HCV infection with liver fibrosis (HCVFIB4>1.4; OR = 2.16, 95% CI: 1.22-3.82, p = 0.008), or (HCVAPRI>0.5; OR = 3.40, 95% CI: 1.28-9.06, p = 0.014) and elevated anti-HCV S/CO ratio (anti-HCVS/CO>10.0; OR = 1.72, 95% CI: 1.01-2.93, p = 0.045) was associated with atherosclerosis. CONCLUSIONS HCV infection with metabolic syndrome, liver fibrosis and elevated anti-HCV S/CO ratio was associated with atherosclerosis.
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Affiliation(s)
- Chih-Wen Wang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Hsing Hung
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Hung Kuo
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming Lung-Yu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital; School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [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: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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10
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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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11
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Jussila A, Zhang B, Kirti S, Atit R. Tissue fibrosis associated depletion of lipid-filled cells. Exp Dermatol 2024; 33:e15054. [PMID: 38519432 PMCID: PMC10977660 DOI: 10.1111/exd.15054] [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: 10/03/2023] [Revised: 02/06/2024] [Accepted: 02/29/2024] [Indexed: 03/24/2024]
Abstract
Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.
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Affiliation(s)
- Anna Jussila
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Brian Zhang
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Sakin Kirti
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Radhika Atit
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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12
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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13
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Guariglia M, Saba F, Rosso C, Bugianesi E. Molecular Mechanisms of Curcumin in the Pathogenesis of Metabolic Dysfunction Associated Steatotic Liver Disease. Nutrients 2023; 15:5053. [PMID: 38140312 PMCID: PMC10745597 DOI: 10.3390/nu15245053] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/23/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition characterized by insulin resistance, oxidative stress, chronic low-grade inflammation, and sometimes fibrosis. To date, no effective pharmacological therapy has been approved for the treatment of metabolic-associated steatohepatitis (MASH), the progressive form of MASLD. Recently, numerous in vitro and in vivo studies have described the efficacy of nutraceutical compounds in the diet has been tested. Among them, curcumin is the most widely used polyphenol in the diet showing potent anti-inflammatory and antifibrotic activities. This review aims to summarize the most important basic studies (in vitro and animal models studies), describing the molecular mechanisms by which curcumin acts in the context of MASLD, providing the rationale for its effective translational use in humans.
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Affiliation(s)
| | | | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (M.G.); (F.S.)
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (M.G.); (F.S.)
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14
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Yamanaka Y, Tajima T, Tsujimura Y, Naito T, Mano Y, Tsukamoto M, Zenke Y, Sakai A. Adiponectin inhibits fibrosis of the palmar aponeurosis in Dupuytren's contracture in male patients. Bone Joint Res 2023; 12:486-493. [PMID: 37536684 PMCID: PMC10400293 DOI: 10.1302/2046-3758.128.bjr-2022-0449.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/05/2023] Open
Abstract
Aims Dupuytren's contracture is characterized by increased fibrosis of the palmar aponeurosis, with eventual replacement of the surrounding fatty tissue with palmar fascial fibromatosis. We hypothesized that adipocytokines produced by adipose tissue in contact with the palmar aponeurosis might promote fibrosis of the palmar aponeurosis. Methods We compared the expression of the adipocytokines adiponectin and leptin in the adipose tissue surrounding the palmar aponeurosis of male patients with Dupuytren's contracture, and of male patients with carpal tunnel syndrome (CTS) as the control group. We also examined the effects of adiponectin on fibrosis-related genes and proteins expressed by fibroblasts in the palmar aponeurosis of patients with Dupuytren's contracture. Results Adiponectin expression in the adipose tissue surrounding the palmar aponeurosis was significantly lower in patients with Dupuytren's contracture than in those with CTS. The expression of fibrosis-related genes and proteins, such as types 1 and 3 collagen and α-smooth muscle actin, was suppressed in a concentration-dependent manner by adding AdipoRon, an adiponectin receptor agonist. The expression of fibrosis-related genes and proteins was also suppressed by AdipoRon in the in vitro model of Dupuytren's contracture created by adding TGF-β to normal fibroblasts collected from patients with CTS. Conclusion Fibrosis of the palmar aponeurosis in Dupuytren's contracture in males may be associated with adiponectin expression in the adipose tissue surrounding the palmar aponeurosis. Although fibroblasts within the palmar aponeurosis are often the focus of attention when elucidating the pathogenesis of Dupuytren's contracture, adiponectin expression in adipose tissues warrants closer attention in future research.
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Affiliation(s)
- Yoshiaki Yamanaka
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Takafumi Tajima
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Yoshitaka Tsujimura
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Toichiro Naito
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Yosuke Mano
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Manabu Tsukamoto
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Yukichi Zenke
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Akinori Sakai
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
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15
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Cheng C, Wu Y, Wang X, Xue Q, Huang Y, Liao F, Wang X, Duan Q, Miao C. RNA methylations in hepatic fibrosis, a gradually emerging new treatment strategy. Cell Biosci 2023; 13:126. [PMID: 37420298 DOI: 10.1186/s13578-023-01066-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 06/06/2023] [Indexed: 07/09/2023] Open
Abstract
BACKGROUND Hepatic fibrosis (HF) is a pathological process caused by excessive accumulation of extracellular matrix caused by a series of causes, leading to the formation of fiber scar. RNA methylation is a newly discovered epigenetic modification that exists widely in eukaryotes and prokaryotes and plays a crucial role in the pathogenesis of many diseases. RESULTS The occurrence and development of HF are regulated by many factors, including excessive deposition of extracellular matrix, activation of hepatic stellate cells, inflammation, and oxidative stress. RNA methylations of different species have become a crucial regulatory mode of transcript expression, And participate in the pathogenesis of tumors, nervous system diseases, autoimmune diseases, and other diseases. In addition, there are five common types of RNA methylation, but only m6A plays a crucial regulatory role in HF. The pathophysiological regulation of m6A on HF is achieved by the combination of the methylated transferase, demethylated enzyme, and methylated reading protein. CONCLUSIONS RNA methylated methyltransferase, demethylase, and reading protein extensively affect the pathological mechanism of HF, which may be a new therapeutic and diagnostic target, representing a new class of therapeutic strategies.
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Affiliation(s)
- Chenglong Cheng
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Yajie Wu
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Xin Wang
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Qiuyun Xue
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Yurong Huang
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Faxue Liao
- Department of Orthopaedics, The First Affiliated Hospital, Anhui Medical University, Hefei, China.
- Anhui Public Health Clinical Center, Hefei, China.
| | - Xiao Wang
- Department of Clinical Nursing, School of Nursing, Anhui University of Chinese Medicine, Hefei, China.
| | - Qiangjun Duan
- Department of Experimental (Practical Training) Teaching Center, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.
| | - Chenggui Miao
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.
- Institute of Rheumatism, Anhui University of Chinese Medicine, Hefei, China.
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16
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Huang X, Chen H, Wen S, Dong M, Zhou L, Yuan X. Therapeutic Approaches for Nonalcoholic Fatty Liver Disease: Established Targets and Drugs. Diabetes Metab Syndr Obes 2023; 16:1809-1819. [PMID: 37366486 PMCID: PMC10290856 DOI: 10.2147/dmso.s411400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), as a multisystemic disease, is the most prevalent chronic liver disease characterized by extremely complex pathogenic mechanisms and multifactorial etiology, which often develops as a consequence of obesity, metabolic syndrome. Pathophysiological mechanisms involved in the development of NAFLD include diet, obesity, insulin resistance (IR), genetic and epigenetic determinants, intestinal dysbiosis, oxidative/nitrosative stress, autophagy dysregulation, hepatic inflammation, gut-liver axis, gut microbes, impaired mitochondrial metabolism and regulation of hepatic lipid metabolism. Some of the new drugs for the treatment of NAFLD are introduced here. All of them achieve therapeutic objectives by interfering with certain pathophysiological pathways of NAFLD, including fibroblast growth factors (FGF) analogues, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon-like peptide-1 (GLP-1) agonists, G protein-coupled receptors (GPCRs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), farnesoid X receptor (FXR), fatty acid synthase inhibitor (FASNi), antioxidants, etc. This review describes some pathophysiological mechanisms of NAFLD and established targets and drugs.
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Affiliation(s)
- Xiaojing Huang
- Graduate School of Fudan University, Shanghai, People’s Republic of China
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Huiling Chen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Meiyuan Dong
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Xinlu Yuan
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
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Qin L, Wu J, Sun X, Huang X, Huang W, Weng C, Cai J. The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease. Front Cardiovasc Med 2023; 10:1119005. [PMID: 37180779 PMCID: PMC10169694 DOI: 10.3389/fcvm.2023.1119005] [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: 12/08/2022] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by an excessive accumulation of fat in the liver, which is becoming a major global health problem, affecting about a quarter of the population. In the past decade, mounting studies have found that 25%-40% of NAFLD patients have cardiovascular disease (CVD), and CVD is one of the leading causes of death in these subjects. However, it has not attracted enough awareness and emphasis from clinicians, and the underlying mechanisms of CVD in NAFLD patients remain unclear. Available research reveals that inflammation, insulin resistance, oxidative stress, and glucose and lipid metabolism disorders play indispensable roles in the pathogenesis of CVD in NAFLD. Notably, emerging evidence indicates that metabolic organ-secreted factors, including hepatokines, adipokines, cytokines, extracellular vesicles, and gut-derived factors, are also involved in the occurrence and development of metabolic disease and CVD. Nevertheless, few studies have focused on the role of metabolic organ-secreted factors in NAFLD and CVD. Therefore, in this review, we summarize the relationship between metabolic organ-secreted factors and NAFLD as well as CVD, which is beneficial for clinicians to comprehensive and detailed understanding of the association between both diseases and strengthen management to improve adverse cardiovascular prognosis and survival.
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Affiliation(s)
| | | | | | | | | | - Chunyan Weng
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
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18
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Yu Q, Dai Q, Huang Z, Li C, Yan L, Fu X, Wang Q, Zhang Y, Cai L, Yang Z, Xiao R. Microfat exerts an anti-fibrotic effect on human hypertrophic scar via fetuin-A/ETV4 axis. J Transl Med 2023; 21:231. [PMID: 37004048 PMCID: PMC10064544 DOI: 10.1186/s12967-023-04065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND Hypertrophic scar is a fibrotic disease following wound healing and is characterized by excessive extracellular matrix deposition. Autologous microfat grafting proves an effective strategy for the treatment thereof as it could improve the texture of scars and relieve relevant symptoms. This study aims to explore the potential mechanisms underlying the anti-fibrotic effect of microfat on hypertrophic scars. METHODS In this study, we injected microfat into transplanted hypertrophic scars in mouse models and investigated the subsequent histological changes and differential expression of mRNAs therein. As for in vitro studies, we co-cultured microfat and hypertrophic scar fibroblasts (HSFs) and analyzed molecular profile changes in HSFs co-cultured with microfat by RNA sequencing. Moreover, to identify the key transcription factors (TFs) which might be responsible for the anti-fibrotic function of microfat, we screened the differentially expressed TFs and transfected HSFs with lentivirus to overexpress or knockdown certain differentially expressed TFs. Furthermore, comparative secretome analyses were conducted to investigate the proteins secreted by co-cultured microfat; changes in gene expression of HSFs were examined after the administration of the potential anti-fibrotic protein. Finally, the relationship between the key TF in HSFs and the microfat-secreted anti-fibrotic adipokine was analyzed. RESULTS The anti-fibrotic effect of microfat was confirmed by in vivo transplanted hypertrophic scar models, as the number of α-SMA-positive myofibroblasts was decreased and the expression of fibrosis-related genes downregulated. Co-cultured microfat suppressed the extracellular matrix production of HSFs in in vitro experiment, and the transcription factor ETV4 was primarily differentially expressed in HSFs when compared with normal skin fibroblasts. Overexpression of ETV4 significantly decreased the expression of fibrosis-related genes in HSFs at both mRNA and protein levels. Fetuin-A secreted by microfat could also downregulate the expression of fibrosis-related genes in HSFs, partially through upregulating ETV4 expression. CONCLUSIONS Our results demonstrated that transcription factor ETV4 is essential for the anti-fibrotic effect of microfat on hypertrophic scars, and that fetuin-A secreted by microfat could suppress the fibrotic characteristic of HSFs through upregulating ETV4 expression. Microfat wields an alleviative influence over hypertrophic scars via fetuin-A/ETV4 axis.
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Affiliation(s)
- Qian Yu
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qiang Dai
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Department of Burns and Plastic Surgery, Beijing Jishuitan Hospital, Beijing, People's Republic of China
| | - Zonglin Huang
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Chen Li
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Li Yan
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xin Fu
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qian Wang
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yi Zhang
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Lei Cai
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China.
| | - Zhigang Yang
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China.
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
| | - Ran Xiao
- Research Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China.
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
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Kim KE, Lee J, Shin HJ, Jeong EA, Jang HM, Ahn YJ, An HS, Lee JY, Shin MC, Kim SK, Yoo WG, Kim WH, Roh GS. Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice. Hepatology 2023; 77:888-901. [PMID: 35560370 PMCID: PMC9936980 DOI: 10.1002/hep.32569] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/19/2022] [Accepted: 05/08/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. APPROACH AND RESULTS Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. CONCLUSIONS LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.
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Affiliation(s)
- Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Jaewoong Lee
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Hye Min Jang
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Yu Jeong Ahn
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Jong Youl Lee
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy , Research Institute of Pharmaceutical Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Soo Kyoung Kim
- Department of Internal Medicine , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Won Gi Yoo
- Department of Parasitology and Tropical Medicine , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
| | - Won Ho Kim
- Division of Cardiovascular Diseases , Center for Biomedical Sciences , Korea National Institute of Health , Cheongju , Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea
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20
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Nguyen TK, Phung HH, Choi WJ, Ahn HC. Network Pharmacology and Molecular Docking Study on the Multi-Target Mechanisms of Aloe vera for Non-Alcoholic Steatohepatitis Treatment. PLANTS (BASEL, SWITZERLAND) 2022; 11:3585. [PMID: 36559697 PMCID: PMC9783676 DOI: 10.3390/plants11243585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 06/17/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease with limited treatment options. The widely distributed plant Aloe vera has shown protective effects against NASH in animals, yet the precise mechanism remains unknown. In this study, we investigated the potential mechanisms underlying the anti-NASH effects of Aloe vera using a network pharmacology and molecular docking approach. By searching online databases and analyzing the Gene Expression Omnibus dataset, we obtained 260 Aloe vera-NASH common targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the common targets were strongly associated with the key pathological processes implicated in NASH, including lipid and glucose metabolism, inflammation, apoptosis, oxidative stress, and liver fibrosis. Four core proteins, AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor alpha (TNFα), transcription factor c-Jun, and tumor suppressor protein p53, were identified from compound-target-pathway and protein-protein interaction networks. Molecular docking analysis verified that the active ingredients of Aloe vera were able to interact with the core proteins, especially AKT1 and TNFα. The results demonstrate the multi-compound, multi-target, and multi-pathway mechanisms of Aloe vera against NASH. Our study has shown the scientific basis for further experiments in terms of the mechanism to develop Aloe vera-based natural products as complementary treatments for NASH. Furthermore, it identifies novel drug candidates based on the structures of Aloe vera's active compounds.
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Thin KN, Tran A, Li J, Lee EY, Yang H, Rui F, Liu C, Stave CD, Cheung RC, Nguyen MH. Increased Risk of Liver-Related Outcomes in Chronic Hepatitis B Patients with Metabolic Syndrome: A Systematic Review and Meta-Analysis. Dig Dis 2022; 40:745-753. [PMID: 34986486 PMCID: PMC9808743 DOI: 10.1159/000521768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 01/03/2022] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Chronic hepatitis B (CHB) patients with metabolic syndrome (MetS) may present increased risk of liver-related outcomes (LROs), but prior studies were limited by small sample size and/or conflicting results. Using a systematic review and meta-analytic approach, we aimed to determine the association between MetS and LROs in CHB. METHODS Two researchers independently screened studies from the PubMed, Embase, Web of Science, and Cochrane Library databases from inception to January 21, 2020, and extracted the data. Estimates were pooled using a random-effects model. RESULTS We screened 2,228 articles and included 10 eligible studies (18,360 CHB patients, 2,557 with MetS). MetS was significantly associated with LROs overall (odds ratio = 2.45, 95% confidence interval = 1.39-4.32) but not the individual LRO components but subgroup analyses were limited by small study numbers. DISCUSSION/CONCLUSION MetS is associated with almost 3-folds higher risk of LROs in CHB and should be considered in management decisions. However, additional studies are needed.
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Affiliation(s)
- Khin Naing Thin
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA,Department of Hepatology, Yangon Specialty Hospital, Yangon, Myanmar/Burma
| | - Andrew Tran
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA,Duke University, Durham, North Carolina, USA
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Eunice Yewon Lee
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Hongli Yang
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong Frist Medical University, Jinan, China
| | - Fajuan Rui
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong Frist Medical University, Jinan, China,Department of Infectious Disease, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanli Liu
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong Frist Medical University, Jinan, China,Department of Infectious Disease, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Christopher D. Stave
- Lane Medical Library, Stanford University School of Medicine, Stanford, California, USA
| | - Ramsey C. Cheung
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Palo Alto Veterans Affairs Medical Center, Palo Alto, California, USA,*Ramsey C. Cheung,
| | - Mindie H. Nguyen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA,Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, USA,**Mindie H. Nguyen,
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22
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Adipokines in Non-Alcoholic Fatty Liver Disease: Are We on the Road toward New Biomarkers and Therapeutic Targets? BIOLOGY 2022; 11:biology11081237. [PMID: 36009862 PMCID: PMC9405285 DOI: 10.3390/biology11081237] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/04/2022]
Abstract
Simple Summary Non-alcoholic fatty liver disease (NAFLD) is an unmet medical need due to its increasingly high incidence, severe clinical consequences, and the absence of feasible diagnostic tools and effective drugs. This review summarizes the preclinical and clinical data on adipokines, cytokine-like hormones secreted by adipose tissue, and NAFLD. The aim is to establish the potential of adipokines as diagnostic and prognostic biomarkers, as well as their potential as therapeutic targets for NAFLD. The limitations of current research are also discussed, and future perspectives are outlined. Abstract Non-alcoholic fatty liver disease (NAFLD) has become the major cause of chronic hepatic illness and the leading indication for liver transplantation in the future decades. NAFLD is also commonly associated with other high-incident non-communicable diseases, such as cardiovascular complications, type 2 diabetes, and chronic kidney disease. Aggravating the socio-economic impact of this complex pathology, routinely feasible diagnostic methodologies and effective drugs for NAFLD management are unavailable. The pathophysiology of NAFLD, recently defined as metabolic associated fatty liver disease (MAFLD), is correlated with abnormal adipose tissue–liver axis communication because obesity-associated white adipose tissue (WAT) inflammation and metabolic dysfunction prompt hepatic insulin resistance (IR), lipid accumulation (steatosis), non-alcoholic steatohepatitis (NASH), and fibrosis. Accumulating evidence links adipokines, cytokine-like hormones secreted by adipose tissue that have immunometabolic activity, with NAFLD pathogenesis and progression; however, much uncertainty still exists. Here, the current knowledge on the roles of leptin, adiponectin, ghrelin, resistin, retinol-binding protein 4 (RBP4), visfatin, chemerin, and adipocyte fatty-acid-binding protein (AFABP) in NAFLD, taken from preclinical to clinical studies, is overviewed. The effect of therapeutic interventions on adipokines’ circulating levels are also covered. Finally, future directions to address the potential of adipokines as therapeutic targets and disease biomarkers for NAFLD are discussed.
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Abstract
Adipose tissue is a complex heterogeneous tissue composed of adipocytes along with several non-adipocyte populations, including blood, stromal, endothelial, and progenitor cells, as well as extracellular matrix (ECM) components. As obesity progresses, the adipose tissue expands dynamically through adipocyte hypertrophy and/or hyperplasia. This expansion requires continuous ECM remodeling to properly accommodate the size increase as well as functional changes. Upon reaching a hypertrophic threshold beyond the adipocyte buffering capacity, excess ECM components are deposited, causing fibrosis and ultimately resulting in unhealthy metabolic maladaptation. These complex ECM remodeling processes in adipose tissues are regulated by the local environment, several key mediators, and genetic factors that are closely linked to insulin sensitivity. It is crucial to understand how adipocytes interact with nonadipocyte populations and various mediators (i.e., immune cells, ECM components, and adipokines) during these processes. This mini-review provides an overview of the latest research into the biology of obesity-induced adipose tissue fibrosis and its related clinical manifestations, providing insight for further studies aimed at controlling metabolic syndrome and its comorbidities.
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Affiliation(s)
- Yutaka Hasegawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
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24
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Influence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration. Nat Commun 2022; 13:2931. [PMID: 35614135 PMCID: PMC9132900 DOI: 10.1038/s41467-022-30629-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis. Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.
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25
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Fang D, Tang W, Zhao X, Sun H, Gu T, Bi Y. Gender differences in the association of body composition and biopsy-proved nonalcoholic steatohepatitis. Hepatol Int 2022; 16:337-347. [PMID: 35201574 DOI: 10.1007/s12072-021-10265-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/20/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIM Body composition was associated with nonalcoholic steatohepatitis (NASH), but results were controversial probably due to gender differences. Hence, we aim to explore the association of body composition and NASH in males and females. METHODS We conducted a cross-sectional analysis of obese subjects undergone liver biopsy. According to NASH Clinical Research Network system, subjects were categorized as Normal Control (NC), non-NASH or NASH. Body composition was accessed by dual-energy X-ray absorptiometry. RESULTS This study enrolled 336 subjects (mean age 32.0 years, mean BMI 39.15 kg/m2, female, 64.0%). Males have lower relative muscle mass (RMM 55.21 ± 4.07%) and females have higher android to gynoid ratio (AGR, 0.82 ± 0.21) in NASH when compared with non-NASH (RMM 57.49 ± 4.75%; AGR 0.7 ± 0.15) and NC (RMM 58.69 ± 4.09%; AGR 0.66 ± 0.19, p < 0.05 for each). After adjusting for confounding factors, low RMM was the independent risk factor for NASH in males (odds ratio [OR] 0.550; 95% confidence interval [CI] 0.312-0.970), high AGR was the independent risk factor for NASH in females (OR 1.694; 95% CI 1.073-2.674). Further, RMM in males and AGR in females, respectively, was associated with liver steatosis and activity, but not with fibrosis. ROC curve revealed that the optimal cutoff value of RMM was 58.09% in males and AGR was 0.92 in females for predicting NASH. CONCLUSIONS We firstly revealed that low RMM and high AGR were the independent risk factors for NASH in males and females, respectively, indicating that sex-specific interventions for improving body composition may reduce the risk of NASH in obese subjects.
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Affiliation(s)
- Da Fang
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Wenjuan Tang
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaoyu Zhao
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Haixiang Sun
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Tianwei Gu
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
| | - Yan Bi
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China. .,Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
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26
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Vaspin attenuates steatosis-induced fibrosis via GRP78 receptor by targeting AMPK signaling pathway. J Physiol Biochem 2022; 78:185-197. [PMID: 35001345 DOI: 10.1007/s13105-021-00852-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/13/2021] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is rapidly becoming a public health problem. An imbalance in lipid distribution to the hepatocytes and metabolism causes hepatocyte steatosis. Vaspin is a newly discovered adipokine that has been linked to a variety of metabolic disorders. The effects of vaspin on steatosis and fibrosis pathogenesis and related mechanisms are unclear. Thus, this study investigated the molecular mechanism of vaspin on hepatocyte steatosis and fibrosis. HepG2 cells were treated with 1.2 mM free fatty acid and the intracellular lipid values were measured by flow cytometry and Nile red assay. RT-qPCR was used to assess the effect of vaspin and blocking of the GRP78 receptor on the expression of lipogenesis, oxidation, uptake, and secretion of fatty acid (FA), as well as AMPK activity. In co-cultured HepG2 and LX-2 cell lines, the expression of main proteins of hepatocyte fibrosis was analyzed using Western blot analysis. In the HepG2 cell line, we discovered that vaspin increased oxidation, FA secretion and gene expression, and AMPK activity and decreased lipogenesis and FA uptake and gene expression. Western blot analysis in co-cultured HepG2 and LX-2 cell lines showed that α-SMA and TGF-β1 protein expression decreased. The data demonstrated that vaspin acts as a novel regulator of hepatocyte steatosis through the GRP78 receptor, effectively reducing hepatocyte fibrosis through AMPK activation and decreasing NF-κB gene expression.
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27
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Iacob SA, Iacob DG. Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients - a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown. Front Endocrinol (Lausanne) 2022; 13:814209. [PMID: 35355551 PMCID: PMC8959898 DOI: 10.3389/fendo.2022.814209] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and is one of the most prevalent comorbidities in HIV and HBV infected patients. HIV plays an early and direct role in the development of metabolic syndrome by disrupting the mechanism of adipogenesis and synthesis of adipokines. Adipokines, molecules that regulate the lipid metabolism, also contribute to the progression of NAFLD either directly or via hepatic organokines (hepatokines). Most hepatokines play a direct role in lipid homeostasis and liver inflammation but their role in the evolution of NAFLD is not well defined. The role of HBV in the pathogenesis of NAFLD is controversial. HBV has been previously associated with a decreased level of triglycerides and with a protective role against the development of steatosis and metabolic syndrome. At the same time HBV displays a high fibrogenetic and oncogenetic potential. In the HIV/HBV co-infection, the metabolic changes are initiated by mitochondrial dysfunction as well as by the fatty overload of the liver, two interconnected mechanisms. The evolution of NAFLD is further perpetuated by the inflammatory response to these viral agents and by the variable toxicity of the antiretroviral therapy. The current article discusses the pathogenic changes and the contribution of the hepatokine/adipokine axis in the development of NAFLD as well as the implications of HIV and HBV infection in the breakdown of the hepatokine/adipokine axis and NAFLD progression.
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Affiliation(s)
- Simona Alexandra Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, National Institute of Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Romania
| | - Diana Gabriela Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, Emergency University Hospital, Bucharest, Romania
- *Correspondence: Diana Gabriela Iacob,
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Delgado ME, Cárdenas BI, Farran N, Fernandez M. Metabolic Reprogramming of Liver Fibrosis. Cells 2021; 10:3604. [PMID: 34944111 PMCID: PMC8700241 DOI: 10.3390/cells10123604] [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: 11/16/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.
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Affiliation(s)
- M. Eugenia Delgado
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
| | | | | | - Mercedes Fernandez
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
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29
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Torre P, Motta BM, Sciorio R, Masarone M, Persico M. Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System. Front Med (Lausanne) 2021; 8:781567. [PMID: 34957156 PMCID: PMC8695879 DOI: 10.3389/fmed.2021.781567] [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: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
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Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Benedetta Maria Motta
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Baronissi, Italy
| | - Roberta Sciorio
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
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Chen YC, Hsu CW, Jeng WJ, Lin CY. Advanced Liver Fibrosis Is Associated with Necroinflammatory Grade but Not Hepatic Steatosis in Chronic Hepatitis B Patients. Dig Dis Sci 2021; 66:4492-4500. [PMID: 33569664 DOI: 10.1007/s10620-020-06761-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/06/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Patients with chronic hepatitis B (CHB) are at an increased risk of disease progression. The influence of hepatic steatosis (HS) to liver fibrosis was controversial. We aim to investigate the association between HS and liver fibrosis and explore the predicting factors for advanced fibrosis. METHODS CHB patients undergoing liver biopsy with complete assessments of HS, necroinflammation grade [histological activity index (HAI) score], and fibrosis stage were retrospectively recruited. Logistic regression analysis was performed to determine the factors associated with advanced liver fibrosis. RESULTS In this cohort of 672 patients, 342 (50.9%) had HS and 267 (39.4%) were of advanced liver fibrosis. Age [odds ratio (OR) 1.026, 95% confidence interval (CI) 1.007-1.046, p = 0.008], body mass index (BMI, OR 1.091, 95% CI 1.026-1.159, p = 0.005), genotype (C vs. B) (OR 2.790, 95% CI 1.847-4.214, p < 0.001), platelet (OR 0.986, 95% CI 0.982-0.991, p < 0.001), and HAI score (OR 1.197, 95% CI 1.114-1.285, p < 0.001) were independent factors for advanced liver fibrosis in multivariate logistic regression analysis. HAI score was also a significantly associated factor for significant liver fibrosis in non-cirrhotic subpopulation (OR 1.578, 95% CI 1.375-1.810, p < 0.001). HS was not related to advanced/significant liver fibrosis in overall/non-cirrhotic population (p > 0.05). CONCLUSIONS Significant or advanced liver fibrosis is associated with grade of necroinflammation but not with HS in CHB patients.
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Affiliation(s)
- Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and University, Linkou, No. 5, Fu Hsing Street, Guishan Dist., Taoyuan City, 33302, Taiwan, ROC. .,College of Medicine, Guishan Dist, Chang Gung University, No. 259, Wen Hua 1st Rd, Taoyuan City, 33302, Taiwan, Republic of China.
| | - Chao-Wei Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and University, Linkou, No. 5, Fu Hsing Street, Guishan Dist., Taoyuan City, 33302, Taiwan, ROC.,College of Medicine, Guishan Dist, Chang Gung University, No. 259, Wen Hua 1st Rd, Taoyuan City, 33302, Taiwan, Republic of China
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and University, Linkou, No. 5, Fu Hsing Street, Guishan Dist., Taoyuan City, 33302, Taiwan, ROC.,College of Medicine, Guishan Dist, Chang Gung University, No. 259, Wen Hua 1st Rd, Taoyuan City, 33302, Taiwan, Republic of China
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and University, Linkou, No. 5, Fu Hsing Street, Guishan Dist., Taoyuan City, 33302, Taiwan, ROC.,College of Medicine, Guishan Dist, Chang Gung University, No. 259, Wen Hua 1st Rd, Taoyuan City, 33302, Taiwan, Republic of China
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31
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The Hepatic Stellate Cells (HSTCs) and Adipose-derived Mesenchymal Stem Cells (ASCs) Axis as a Potential Major Driver of Metabolic Syndrome - Novel Concept and Therapeutic Implications. Stem Cell Rev Rep 2021; 18:1417-1422. [PMID: 34822062 PMCID: PMC9033713 DOI: 10.1007/s12015-021-10304-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2021] [Indexed: 11/27/2022]
Abstract
Abstract Herein, we would like to introduce a novel concept for the prevention and treatment of metabolic syndrome, which is based on molecular relationship between liver and adipose tissue. Particularly, we believe, that unravelling the molecular crosstalk between hepatokines and adipokines will allow to better understand the pathophysiology of metabolic diseases and allow to develop novel, effective therapeutic solutions against obesity and metabolic syndrome. Graphical Abstract Inter-organ communication on the level of stem progenitor cells-hepatic stellate cells (HSTCs) and adipose-derived progenitors (ASCs) could represents a key mechanism involved in controlling glucose tolerance as well as insulin sensitivity. ![]()
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32
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The Mechanism of Leptin on Inhibiting Fibrosis and Promoting Browning of White Fat by Reducing ITGA5 in Mice. Int J Mol Sci 2021; 22:ijms222212353. [PMID: 34830238 PMCID: PMC8618604 DOI: 10.3390/ijms222212353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson’s trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-β (TGF-β) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism.
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33
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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34
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The Controversial Role of Adiponectin in Appetite Regulation of Animals. Nutrients 2021; 13:nu13103387. [PMID: 34684387 PMCID: PMC8539471 DOI: 10.3390/nu13103387] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/05/2021] [Accepted: 09/23/2021] [Indexed: 12/20/2022] Open
Abstract
Eating disorders and obesity are important health problems with a widespread global epidemic. Adiponectin (AdipoQ), the most abundant adipokine in the plasma, plays important roles in the regulation of energy homeostasis, glucose metabolism and lipid metabolism. Plasma adiponectin concentration is negatively associated with obesity and binge eating disorder. There is a growing interest in the appetite regulation function of adiponectin. However, the effect of AdipoQ on feeding behavior is controversial and closely related to nutritional status and food composition. In this review, we summarize the literatures about the discovery, structure, tissue distribution, receptors and regulation of nutritional status, and focus on the biological function of adiponectin in the regulation of food intake in the central and peripheral system.
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35
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Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review. Int J Mol Sci 2021; 22:ijms22115801. [PMID: 34071550 PMCID: PMC8198390 DOI: 10.3390/ijms22115801] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/15/2021] [Accepted: 05/24/2021] [Indexed: 12/24/2022] Open
Abstract
Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.
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Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021; 184:2537-2564. [PMID: 33989548 DOI: 10.1016/j.cell.2021.04.015] [Citation(s) in RCA: 1057] [Impact Index Per Article: 264.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/21/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT 06520, USA.
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37
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Abstract
Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.
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Affiliation(s)
- Min-Hyun Kim
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
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38
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Yang YJ, Kim DJ. An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia. Int J Mol Sci 2021; 22:ijms22052604. [PMID: 33807573 PMCID: PMC7961345 DOI: 10.3390/ijms22052604] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
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Affiliation(s)
- Young Joo Yang
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
- Correspondence:
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39
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Livzan MA, Krolevets TS, Mozgovoy SI, Nikolaev NA, Nelidova AV. [Features of intestinal microbiota disorders in the development of metabolic disorders in non-alcoholic fatty liver disease]. TERAPEVT ARKH 2021; 93:222-227. [PMID: 36286641 DOI: 10.26442/00403660.2021.02.200614] [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: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 11/22/2022]
Abstract
We discussed about the term intestinal permeability like as the mucosal barrier a single structural and functional conception that includes the layer of mucus, the indigenous microbiota and the epithelium of the mucosa in this publication. Information was presented about the role of the microbiota, the composition of intestinal mucus, epithelial cells and proteins of tight junctions which lead to various metabolic diseases. The complex pathogenetic interactions are formed between the intestinal mucosal barrier, metabolic disorders such as non-alcoholic fatty liver disease and cardiovascular diseases. The complex researches and modification of this interactions will allow to create personalized approaches and to prevent of these diseases.
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40
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Blázovics A. Alcoholic liver disease. INFLUENCE OF NUTRIENTS, BIOACTIVE COMPOUNDS, AND PLANT EXTRACTS IN LIVER DISEASES 2021:57-82. [DOI: 10.1016/b978-0-12-816488-4.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Fernández-Mincone T, Contreras-Briceño F, Espinosa-Ramírez M, García-Valdés P, López-Fuenzalida A, Riquelme A, Arab JP, Cabrera D, Arrese M, Barrera F. Nonalcoholic fatty liver disease and sarcopenia: pathophysiological connections and therapeutic implications. Expert Rev Gastroenterol Hepatol 2020; 14:1141-1157. [PMID: 32811209 DOI: 10.1080/17474124.2020.1810563] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common liver diseases worldwide. Recent data suggest that loss of skeletal muscle mass and function (i.e. sarcopenia) is highly prevalent and frequently overlooked in NAFLD patients. Experimental and clinical data suggest that the relationship between NAFLD and sarcopenia is pathophysiologically complex and bi-directional and there is a growing interest in unveiling how sarcopenia could influence NAFLD development and progression. AREAS COVERED PubMed/MEDLINE was searched for articles related to concomitant occurrence of NAFLD and sarcopenia between January 2013 and April 2020. Areas covered in this review include: (1) updated sarcopenia diagnosis strategy, (2) discussion of current data on pathophysiological connections between NAFLD and sarcopenia, and (3) analysis of current and future therapeutic implications of this knowledge. EXPERT OPINION Clinical studies describe a consistent association between NAFLD and sarcopenia, although a cause-effect relation remains to be determined. Active implementation of current diagnosis algorithms and optimized treatment can prevent sarcopenia related complications in subjects with NAFLD. Pathogenic pathways implicated in this relation are multiple and complex, a better understanding of them can provide novel biomarkers and targeted therapies that will hopefully have an important impact in NAFLD management.
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Affiliation(s)
- Tiziana Fernández-Mincone
- Laboratorio de Fisiología del Ejercicio, Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Felipe Contreras-Briceño
- Laboratorio de Fisiología del Ejercicio, Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Maximiliano Espinosa-Ramírez
- Laboratorio de Fisiología del Ejercicio, Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Patricio García-Valdés
- Laboratorio de Fisiología del Ejercicio, Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Antonio López-Fuenzalida
- Laboratorio de Fisiología del Ejercicio, Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Arnoldo Riquelme
- Departamento Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile.,Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Daniel Cabrera
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile.,Facultad de Ciencias Médicas, Universidad Bernardo O Higgins , Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile
| | - Francisco Barrera
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
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Xu H, Zhao Q, Song N, Yan Z, Lin R, Wu S, Jiang L, Hong S, Xie J, Zhou H, Wang R, Jiang X. AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis. Nat Commun 2020; 11:5807. [PMID: 33199780 PMCID: PMC7669869 DOI: 10.1038/s41467-020-19668-y] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 10/27/2020] [Indexed: 12/13/2022] Open
Abstract
Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis. Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.
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Affiliation(s)
- Hongjiao Xu
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Qian Zhao
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Nazi Song
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Zhibin Yan
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Runfeng Lin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Shuohan Wu
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Lili Jiang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Sihua Hong
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Junqiu Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Huihao Zhou
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China
| | - Rui Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Xianxing Jiang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China.
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Chon YE, Jung KS, Ha Y, Kim MN, Lee JH, Hwang SG, Ahn SH, Kim DY, Han KH, Park JY. High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis. J Viral Hepat 2020; 27:1119-1126. [PMID: 32558181 DOI: 10.1111/jvh.13345] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/26/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.
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Affiliation(s)
- Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Kyu Sik Jung
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yeonjung Ha
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Mi Na Kim
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Joo Ho Lee
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
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Xie N, Zhang L, Gao W, Huang C, Huber PE, Zhou X, Li C, Shen G, Zou B. NAD + metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther 2020; 5:227. [PMID: 33028824 PMCID: PMC7539288 DOI: 10.1038/s41392-020-00311-7] [Citation(s) in RCA: 473] [Impact Index Per Article: 94.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/04/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.
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Affiliation(s)
- Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Lu Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Wei Gao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Peter Ernst Huber
- CCU Molecular and Radiation Oncology, German Cancer Research Center; Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Xiaobo Zhou
- First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Changlong Li
- West China School of Basic Medical Sciences & Forensic Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Guobo Shen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| | - Bingwen Zou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
- CCU Molecular and Radiation Oncology, German Cancer Research Center; Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
- Department of Thoracic Oncology and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Acierno C, Caturano A, Pafundi PC, Nevola R, Adinolfi LE, Sasso FC. Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.
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Affiliation(s)
- Carlo Acierno
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Ital
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Xiong Y, Lu H, Xu H. Galangin Reverses Hepatic Fibrosis by Inducing HSCs Apoptosis via the PI3K/Akt, Bax/Bcl-2, and Wnt/β-Catenin Pathway in LX-2 Cells. Biol Pharm Bull 2020; 43:1634-1642. [PMID: 32893252 DOI: 10.1248/bpb.b20-00258] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hepatic fibrosis (HF) is a common disease, with currently no available treatment. Galangin, a natural flavonoid extracted from Alpinia officinaruim Hance, has multiple effects demonstrated in previous studies. The aim of the present study was to explore the anti-fibrogenic effect of galangin in vitro, and research its potential molecular mechanisms. LX-2 cells were chosen as an in vitro HF model, and were treated with galangin in different concentrations. Cell viability was analyzed using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis was measured using flow cytometry, and the anti-fibrogenic effect of galangin was determined using RT-quantitative (q)PCR, immunofluorescence, and Western blotting. The results show that the proliferation of LX-2 cells was efficiently inhibited by galangin, and apoptosis was induced in a dose-dependent manner. Both the mRNA and protein expression of alpha-smooth muscle actin (α-SMA) and collagen I were markedly downregulated. Galangin also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and Wnt/β-catenin signaling pathways and increased the Bax/Bcl-2 ratio. The results of this study suggest that galangin has an anti-fibrogenic effect and may represent a promising agent in the treatment of hepatic fibrosis.
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Affiliation(s)
- Yuanguo Xiong
- School of Pharmaceuticals, Hubei University of Chinese Medicine
| | - Hao Lu
- School of Pharmaceuticals, Hubei University of Chinese Medicine
| | - Hanlin Xu
- School of Pharmaceuticals, Hubei University of Chinese Medicine
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Keinicke H, Sun G, Mentzel CMJ, Fredholm M, John LM, Andersen B, Raun K, Kjaergaard M. FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation. Endocr Connect 2020; 9:755-768. [PMID: 32688339 PMCID: PMC7424338 DOI: 10.1530/ec-20-0152] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/19/2020] [Indexed: 12/11/2022]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically worldwide and, subsequently, also the risk of developing non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis and cancer. Today, weight loss is the only available treatment, but administration of fibroblast growth factor 21 (FGF21) analogues have, in addition to weight loss, shown improvements on liver metabolic health but the mechanisms behind are not entirely clear. The aim of this study was to investigate the hepatic metabolic profile in response to FGF21 treatment. Diet-induced obese (DIO) mice were treated with s.c. administration of FGF21 or subjected to caloric restriction by switching from high fat diet (HFD) to chow to induce 20% weight loss and changes were compared to vehicle dosed DIO mice. Cumulative caloric intake was reduced by chow, while no differences were observed between FGF21 and vehicle dosed mice. The body weight loss in both treatment groups was associated with reduced body fat mass and hepatic triglycerides (TG), while hepatic cholesterol was slightly decreased by chow. Liver glycogen was decreased by FGF21 and increased by chow. The hepatic gene expression profiles suggest that FGF21 increased uptake of fatty acids and lipoproteins, channeled TGs toward the production of cholesterol and bile acid, reduced lipogenesis and increased hepatic glucose output. Furthermore, FGF21 appeared to reduce inflammation and regulate hepatic leptin receptor-a expression. In conclusion, FGF21 affected several metabolic pathways to reduce hepatic steatosis and improve hepatic health and markedly more genes than diet restriction (61 vs 16 out of 89 investigated genes).
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Affiliation(s)
- Helle Keinicke
- Insulin and Device Trial Operations, Novo Nordisk A/S, Søborg, Denmark
| | - Gao Sun
- Pharmacology and Histopathology, Novo Nordisk A/S, China
| | - Caroline M Junker Mentzel
- Department of Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Merete Fredholm
- Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Linu Mary John
- Global Obesity and Liver Disease Research, Novo Nordisk A/S, Måløv, Denmark
| | - Birgitte Andersen
- Global Obesity and Liver Disease Research, Novo Nordisk A/S, Måløv, Denmark
| | - Kirsten Raun
- Global Obesity and Liver Disease Research, Novo Nordisk A/S, Måløv, Denmark
| | - Marina Kjaergaard
- Global Obesity and Liver Disease Research, Novo Nordisk A/S, Måløv, Denmark
- Correspondence should be addressed to M Kjaergaard:
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Hepatic steatosis and liver fat contents in liver transplant recipients are associated with serum adipokines and insulin resistance. Sci Rep 2020; 10:12701. [PMID: 32728230 PMCID: PMC7391625 DOI: 10.1038/s41598-020-69571-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 06/23/2020] [Indexed: 12/14/2022] Open
Abstract
Our data about pathogenesis of hepatic steatosis after liver transplantation is scarce. This study aimed to investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients. We investigated the association between insulin resistance, serum adiponectin, insulin, and leptin with hepatic steatosis in a cohort of liver transplant recipients. Homeostatic model assessment of insulin resistance 2 (HOMA 2-IR) was used for estimation of insulin resistance. Hepatic steatosis was determined using ultrasound and controlled attenuation parameter (CAP). A total of 178 patients were included. 79 patients (44.4%) had hepatic steatosis. Serum adiponectin (OR: 0.912; 95% CI 0.869–0.957; P < 0.001), serum leptin (OR: 1.060; 95% CI 1.017–1.102; P = 0.005), HOMA2-IR (OR: 1.671; 95% CI 1.049–2.662; P = 0.031), and post-transplant diabetes mellitus (PTDM) (OR: 5.988; 95% CI 1.680–21.276; P = 0.006) were independently associated with hepatic steatosis after liver transplantation. CAP values were negatively correlated with serum adiponectin (P = 0.011) and positively correlated with serum insulin (P = 0.001), leptin (P < 0.001) and HOMA2-IR (P < 0.001). Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes.
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Data on Adiponectin from 2010 to 2020: Therapeutic Target and Prognostic Factor for Liver Diseases? Int J Mol Sci 2020; 21:ijms21155242. [PMID: 32718097 PMCID: PMC7432057 DOI: 10.3390/ijms21155242] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/13/2022] Open
Abstract
The review describes the role of adiponectin in liver diseases in the presence and absence of surgery reported in the literature in the last ten years. The most updated therapeutic strategies based on the regulation of adiponectin including pharmacological and surgical interventions and adiponectin knockout rodents, as well as some of the scientific controversies in this field, are described. Whether adiponectin could be a potential therapeutic target for the treatment of liver diseases and patients submitted to hepatic resection or liver transplantation are discussed. Furthermore, preclinical and clinical data on the mechanism of action of adiponectin in different liver diseases (nonalcoholic fatty disease, alcoholic liver disease, nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) in the absence or presence of surgery are evaluated in order to establish potential targets that might be useful for the treatment of liver disease as well as in the practice of liver surgery associated with the hepatic resections of tumors and liver transplantation.
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50
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Chan YT, Wang N, Tan HY, Li S, Feng Y. Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era? Front Pharmacol 2020; 11:548. [PMID: 32425789 PMCID: PMC7212390 DOI: 10.3389/fphar.2020.00548] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a progressive liver damage condition that is worth studying widely. It is important to target and alleviate the disease at an early stage before turning into later cirrhosis or liver cancer. There are currently no direct medicines targeting the attenuation or reversal of liver fibrosis, and so there is an urgent need to look into this area. Traditional Chinese Medicine has a long history in using herbal medicines to treat liver diseases including fibrosis. It is time to integrate the ancient wisdom with modern science and technology to look for the best solution to the disease. In this review, the principal concept of the pathology of liver fibrosis will be described, and then some of the single compounds isolated from herbal medicines, including salvianolic acids, oxymatrine, curcumin, tetrandrine, etc. will be discussed from their effects to the molecular mechanism behind. Molecular targets of the compounds are analyzed by network pharmacology approach, and TGFβ/SMAD was identified as the most common pathway. This review serves to summarize the current findings of herbal medicines combining with modern medicines in the area of fibrosis. It hopefully provides insights in further pharmaceutical research directions.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Sha Li
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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