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Duan H, Gong M, Yuan G, Wang Z. Sex Hormone: A Potential Target at Treating Female Metabolic Dysfunction-Associated Steatotic Liver Disease? J Clin Exp Hepatol 2025; 15:102459. [PMID: 39722783 PMCID: PMC11667709 DOI: 10.1016/j.jceh.2024.102459] [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: 08/10/2024] [Accepted: 11/13/2024] [Indexed: 12/28/2024] Open
Abstract
The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising due to rapid lifestyle changes. Although females may be less prone to MASLD than males, specific studies on MASLD in females should still be conducted. Previous research has shown that sex hormone levels are strongly linked to MASLD in females. By reviewing a large number of experimental and clinical studies, we summarized the pathophysiological mechanisms of estrogen, androgen, sex hormone-binding globulin, follicle-stimulating hormone, and prolactin involved in the development of MASLD. We also analyzed the role of these hormones in female MASLD patients with polycystic ovarian syndrome or menopause, and explored the potential of targeting sex hormones for the treatment of MASLD. We hope this will provide a reference for further exploration of mechanisms and treatments for female MASLD from the perspective of sex hormones.
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Affiliation(s)
- Huiyan Duan
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minmin Gong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Yuan
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Khan MM, Khan ZA, Khan MA. Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration. World J Psychiatry 2024; 14:767-783. [PMID: 38984346 PMCID: PMC11230099 DOI: 10.5498/wjp.v14.i6.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024] Open
Abstract
Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
| | - Zaw Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
| | - Mohsin Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
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3
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Chondrogianni ME, Kyrou I, Androutsakos T, Flessa CM, Menenakos E, Chatha KK, Aranan Y, Papavassiliou AG, Kassi E, Randeva HS. Anti-osteoporotic treatments in the era of non-alcoholic fatty liver disease: friend or foe. Front Endocrinol (Lausanne) 2024; 15:1344376. [PMID: 38524631 PMCID: PMC10957571 DOI: 10.3389/fendo.2024.1344376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 01/05/2024] [Indexed: 03/26/2024] Open
Abstract
Over the last years non-alcoholic fatty liver disease (NAFLD) has grown into the most common chronic liver disease globally, affecting 17-38% of the general population and 50-75% of patients with obesity and/or type 2 diabetes mellitus (T2DM). NAFLD encompasses a spectrum of chronic liver diseases, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH; or metabolic dysfunction-associated steatohepatitis, MASH) to fibrosis and cirrhosis with liver failure or/and hepatocellular carcinoma. Due to its increasing prevalence and associated morbidity and mortality, the disease-related and broader socioeconomic burden of NAFLD is substantial. Of note, currently there is no globally approved pharmacotherapy for NAFLD. Similar to NAFLD, osteoporosis constitutes also a silent disease, until an osteoporotic fracture occurs, which poses a markedly significant disease and socioeconomic burden. Increasing emerging data have recently highlighted links between NAFLD and osteoporosis, linking the pathogenesis of NAFLD with the process of bone remodeling. However, clinical studies are still limited demonstrating this associative relationship, while more evidence is needed towards discovering potential causative links. Since these two chronic diseases frequently co-exist, there are data suggesting that anti-osteoporosis treatments may affect NAFLD progression by impacting on its pathogenetic mechanisms. In the present review, we present on overview of the current understanding of the liver-bone cross talk and summarize the experimental and clinical evidence correlating NAFLD and osteoporosis, focusing on the possible effects of anti-osteoporotic drugs on NAFLD.
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Affiliation(s)
- Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Endocrine Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Kyrou
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Health & Life Sciences, Coventry University, Coventry, United Kingdom
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, United Kingdom
- College of Health, Psychology and Social Care, University of Derby, Derby, United Kingdom
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Menenakos
- 5th Surgical Clinic, Department of Surgery, ‘Evgenidion Hospital’, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Kamaljit Kaur Chatha
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Department of Biochemistry and Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Yekaterina Aranan
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Endocrine Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Health & Life Sciences, Coventry University, Coventry, United Kingdom
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4
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Zhao M, Ma L, Honda T, Kato A, Ohshiro T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Tsuji NM, Ishigami M, Fujishiro M. Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet. Dig Dis Sci 2023; 68:155-163. [PMID: 35397697 DOI: 10.1007/s10620-022-07489-6] [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: 12/06/2021] [Accepted: 03/14/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.
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Affiliation(s)
- Meng Zhao
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Lingyun Ma
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Asuka Kato
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.,ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Taichi Ohshiro
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Noriko M Tsuji
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.,Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.,Department of Food Science, Jumonji University, Saitama, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
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Vachliotis ID, Anastasilakis AD, Goulas A, Goulis DG, Polyzos SA. Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications. Diabetes Obes Metab 2022; 24:1702-1720. [PMID: 35589613 DOI: 10.1111/dom.14774] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/01/2022] [Accepted: 05/17/2022] [Indexed: 11/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and osteoporosis are two highly prevalent metabolic diseases. Increasing experimental evidence supports a pathophysiological link between NAFLD and osteoporosis. A key feature could be chronic, low-grade inflammation, which characterizes NAFLD and possibly affects bone metabolism. In this context, several factors, including but not limited to receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, osteopontin and osteocalcin, may serve as mediators. In the clinical setting, most but not all epidemiological evidence indicates that NAFLD is associated with lower bone mineral density or osteoporosis in adults. Although an association between NAFLD and osteoporosis has not yet been established, and thus remains speculative, pharmacological considerations already exist. Some of the current and emerging pharmacological options for NAFLD have shown possible anti-osteoporotic properties (eg, vitamin E, obeticholic acid, semaglutide), while others (eg, pioglitazone, canagliflozin) have been associated with increased risk of fractures and may be avoided in patients with NAFLD and concomitant osteoporosis, especially those at high fracture risk. Conversely, some anti-osteoporotic medications (denosumab) might benefit NAFLD, while others (raloxifene) might adversely affect it and, consequently, may be avoided in patients with osteoporosis and NAFLD. If an association between NAFLD and osteoporosis is established, a medication that could target both diseases would be a great advancement. This review summarizes the main experimental and clinical evidence on the potential association between NAFLD and osteoporosis and focuses on treatment considerations derived from this potential association.
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Affiliation(s)
- Ilias D Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece
| | | | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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6
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Kang F, Zou Q, Huang J. The effects of raloxifene on endothelial function and Inflammation in Postmenopausal women: A Meta-analysis of randomized controlled trials. Exp Gerontol 2021; 159:111682. [PMID: 34973344 DOI: 10.1016/j.exger.2021.111682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND AIM Raloxifene treatment has been reported to be associated with cardiovascular benefits if prescribed to women during the postmenopausal period. However, a final conclusion regarding this hypothesis has not yet been achieved. We conducted a systematic review and meta-analysis to evaluate the effect of raloxifene on the endothelial function and inflammation in postmenopausal women. METHODS We systematically searched the following 4 databases from inception to 23 January 2021 without any language restrictions: Web of Science, PubMed/Medline, Embase and Scopus. The eligible randomized controlled trials (RCTs) reporting the effects of raloxifene on the flow-mediated dilatation (FMD), C-reactive protein (CRP), carotid intima-media thickness (CIMT), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin levels, were included in the final meta-analysis. RESULTS A total of 16 RCTs were included in the final analysis. Raloxifene administration had no significant effect on ICAM-1 and E-selectin levels. However, we observed a decrease of the CIMT (WMD: -0.071 mm, 95% CI: -0.09 to -0.04, P = 0.000), CRP (WMD: -0.342 mg/L, 95% CI: -0.591, -0.094, p = 0.007), and VCAM-1 (WMD: -197.90 mg/L, 95% CI: -269.58 to -126.23, P = 0.000) levels in the intervention versus control groups following the prescription of this pharmacological agent. Moreover, raloxifene treatment resulted in a significant elevation of the FMD (WMD: 1.64%, 95% CI: 0.46 to 2.81, P = 0.006), particularly if the intervention was equal to or exceeded 12 weeks. CONCLUSION Raloxifene might emerge as a potential therapeutic option in the management of endothelial dysfunction and inflammation in postmenopausal women.
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Affiliation(s)
- Fuli Kang
- Department of Gynecology, The Second Hospital of Dalian Medical University, Liaoning, Dalian 116021, China
| | - Qi Zou
- Third Department of Gynecology, Dalian Municipal Women And Children's Medical Center (Group), Liaoning, Dalian 116021, China
| | - Jiazhen Huang
- Department of Gynecology, The Second Hospital of Dalian Medical University, Liaoning, Dalian 116021, China.
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7
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Morán-Costoya A, Proenza AM, Gianotti M, Lladó I, Valle A. Sex Differences in Nonalcoholic Fatty Liver Disease: Estrogen Influence on the Liver-Adipose Tissue Crosstalk. Antioxid Redox Signal 2021; 35:753-774. [PMID: 33736456 DOI: 10.1089/ars.2021.0044] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Significance: Nonalcoholic fatty liver disease (NAFLD) is a hepatic and systemic disorder with a complex multifactorial pathogenesis. Owing to the rising incidence of obesity and diabetes mellitus, the prevalence of NAFLD and its impact on global health care are expected to increase in the future. Differences in NAFLD exist between males and females, and among females depending on their reproductive status. Clinical and preclinical data show that females in the fertile age are more protected against NAFLD, and studies in postmenopausal women and ovariectomized animal models support a protective role for estrogens. Recent Advances: An efficient crosstalk between the liver and adipose tissue is necessary to regulate lipid and glucose metabolism, protecting the liver from steatosis and insulin resistance contributing to NALFD. New advances in the knowledge of sexual dimorphism in liver and adipose tissue are providing interesting clues about the sex differences in NAFLD pathogenesis that could inspire new therapeutic strategies. Critical Issues: Sex hormones influence key master regulators of lipid metabolism and oxidative stress in liver and adipose tissue. All these sex-biased metabolic adjustments shape the crosstalk between liver and adipose tissue, contributing to the higher protection of females to NAFLD. Future Directions: The development of novel drugs based on the protective action of estrogens, but without its feminizing or undesired side effects, might provide new therapeutic strategies for the management of NAFLD. Antioxid. Redox Signal. 35, 753-774.
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Affiliation(s)
- Andrea Morán-Costoya
- Energy Metabolism and Nutrition Group, Department of Fundamental Biology and Health Sciences, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma, Spain.,Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
| | - Ana M Proenza
- Energy Metabolism and Nutrition Group, Department of Fundamental Biology and Health Sciences, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma, Spain.,Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.,Center for Biomedical Research in the Pathophysiology of Obesity and Nutrition Network, Carlos III Health Institute, Madrid, Spain
| | - Magdalena Gianotti
- Energy Metabolism and Nutrition Group, Department of Fundamental Biology and Health Sciences, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma, Spain.,Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.,Center for Biomedical Research in the Pathophysiology of Obesity and Nutrition Network, Carlos III Health Institute, Madrid, Spain
| | - Isabel Lladó
- Energy Metabolism and Nutrition Group, Department of Fundamental Biology and Health Sciences, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma, Spain.,Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.,Center for Biomedical Research in the Pathophysiology of Obesity and Nutrition Network, Carlos III Health Institute, Madrid, Spain
| | - Adamo Valle
- Energy Metabolism and Nutrition Group, Department of Fundamental Biology and Health Sciences, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma, Spain.,Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.,Center for Biomedical Research in the Pathophysiology of Obesity and Nutrition Network, Carlos III Health Institute, Madrid, Spain
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8
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Guillemot-Legris O, Muccioli GG. The oxysterome and its receptors as pharmacological targets in inflammatory diseases. Br J Pharmacol 2021; 179:4917-4940. [PMID: 33817775 DOI: 10.1111/bph.15479] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions, including atherosclerosis, obesity and neurodegenerative diseases, led to a better understanding of their involvement in (patho)physiological processes such as inflammation and immunity. For instance, the characterization of the cholesterol-7α,25-dihydroxycholesterol/GPR183 axis and its implication in immunity represents an important step in the oxysterome study. Besides this axis, others were identified as important in several inflammatory pathologies (such as colitis, lung inflammation and atherosclerosis). However, the oxysterome is a complex system notably due to a redundancy of metabolic enzymes and a wide range of receptors. Indeed, deciphering oxysterol roles and identifying the potential receptor(s) involved in a given pathology remain challenging. Oxysterol properties are very diverse, but most of them could be connected by a common component: inflammation. Here, we review the implication of oxysterol receptors in inflammatory diseases.
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Affiliation(s)
- Owein Guillemot-Legris
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
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9
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Sucedaram Y, Johns EJ, Husain R, Abdul Sattar M, H Abdulla M, Nelli G, Rahim NS, Khalilpourfarshbafi M, Abdullah NA. Exposure to High-Fat Style Diet Induced Renal and Liver Structural Changes, Lipid Accumulation and Inflammation in Intact and Ovariectomized Female Rats. J Inflamm Res 2021; 14:689-710. [PMID: 33716510 PMCID: PMC7944944 DOI: 10.2147/jir.s299083] [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: 12/25/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Purpose We hypothesized that low estrogen levels aggravate obesity-related complications. Diet-induced obesity can cause distinct pathologies, including impaired glucose tolerance, inflammation, and organ injury that leads to fatty liver and chronic kidney diseases. To test this hypothesis, ovariectomized (OVX) rats were fed a high-fat style diet (HFSD), and we examined structural changes and inflammatory response in the kidney and liver. Methods Sprague-Dawley female rats were ovariectomized or sham-operated and divided into four groups: sham-operated rats fed a normal diet (ND); ovariectomized rats fed a normal diet (OVX-ND); sham-operated rats fed a HFSD; ovariectomized rats fed a high-fat style diet (OVX-HFSD). Mean blood pressure and fasting blood glucose were measured on weeks 0 and 10. The rats were sacrificed 10 weeks after initiation of ND or HFSD, the kidney and liver were harvested for histological, immunohistochemical and immunofluorescence studies. Results HFSD-fed rats presented a significantly greater adiposity index compared to their ND counterparts. Liver index, fasting blood glucose and mean blood pressure was increased in OVX-HFSD rats compared to HFSD rats at study terminal. Histological and morphometric studies showed focal interstitial mononuclear cell infiltration in the kidney of HFSD rats with mesangial expansion being greater in the OVX-HFSD rats. Both HFSD fed groups showed increased expressions of renal inflammatory markers, namely TNF-alpha, IL-6 and MCP-1, and infiltrating M1 macrophages with some influence of ovarian hormonal status. HFSD-feeding also caused hepatocellular steatosis which was aggravated in ovariectomized rats fed the same diet. Furthermore, hepatocellular ballooning was observed only in the OVX-HFSD rats. Similarly, HFSD-fed rats showed increased expressions of the inflammatory markers and M1 macrophage infiltration in the liver; however, only IL-6 expression was magnified in the OVX-HFSD. Conclusion Our data suggest that some of the structural changes and inflammatory response in the kidney and liver of rats fed a HFSD are exacerbated by ovariectomy.
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Affiliation(s)
- Yamuna Sucedaram
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
| | - Edward James Johns
- Department of Physiology, University College Cork, Cork, T12 K8AF, Ireland
| | - Ruby Husain
- Department of Physiology, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
| | - Munavvar Abdul Sattar
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, 11800, Pulau Pinang, Malaysia
| | - Mohammed H Abdulla
- Department of Physiology, University College Cork, Cork, T12 K8AF, Ireland
| | - Giribabu Nelli
- Department of Physiology, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
| | - Nur Syahrina Rahim
- Faculty of Medicine & Health Science, Universiti Sains Islam Malaysia, Nilai, 71800, Malaysia
| | | | - Nor Azizan Abdullah
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
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Hypothyroidism-Induced Nonalcoholic Fatty Liver Disease (HIN): Mechanisms and Emerging Therapeutic Options. Int J Mol Sci 2020; 21:ijms21165927. [PMID: 32824723 PMCID: PMC7460638 DOI: 10.3390/ijms21165927] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/14/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an emerging worldwide problem and its association with other metabolic pathologies has been one of the main research topics in the last decade. The aim of this review article is to provide an up-to-date correlation between hypothyroidism and NAFLD. We followed evidence regarding epidemiological impact, immunopathogenesis, thyroid hormone-liver axis, lipid and cholesterol metabolism, insulin resistance, oxidative stress, and inflammation. After evaluating the influence of thyroid hormone imbalance on liver structure and function, the latest studies have focused on developing new therapeutic strategies. Thyroid hormones (THs) along with their metabolites and thyroid hormone receptor β (THR-β) agonist are the main therapeutic targets. Other liver specific analogs and alternative treatments have been tested in the last few years as potential NAFLD therapy. Finally, we concluded that further research is necessary as well as the need for an extensive evaluation of thyroid function in NAFLD/NASH patients, aiming for better management and outcome.
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Ilg MM, Stafford SJ, Mateus M, Bustin SA, Carpenter MJ, Muneer A, Bivalacqua TJ, Ralph DJ, Cellek S. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020; 17:1848-1864. [PMID: 32771352 DOI: 10.1016/j.jsxm.2020.06.022] [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] [Received: 04/22/2020] [Revised: 06/12/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Myofibroblast transformation is a key step in the pathogenesis of Peyronie's disease (PD). Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis. AIM To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-β1)-induced myofibroblast transformation and determine the point of no return. METHODS In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-β1-induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription-quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-β1. OUTCOMES Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts. RESULTS Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-β1 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-β were downregulated after 72 hours, and estrogen receptor -α protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-β1 treatment, whereas vardenafil could prevent only 24 hours after TGF-β1 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-β1 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point. CLINICAL TRANSLATION This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action. STRENGTHS & LIMITATIONS The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays. CONCLUSION This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-β1 treatment can be suggested as a "point of no return" for myofibroblast transformation. Ilg MM, Stafford SJ, Mateus M, et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020;17:1848-1864.
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Affiliation(s)
- Marcus M Ilg
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK.
| | - Simon J Stafford
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK
| | - Marta Mateus
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK
| | - Stephen A Bustin
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK
| | - Michael J Carpenter
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK
| | - Asif Muneer
- Department of Urology, University College London, London, UK; NIHR Biomedical Research Centre, University College London, London, UK
| | - Trinity J Bivalacqua
- James Buchanan Brady Urologic Institute, John Hopkins University, Baltimore, MD, USA
| | - David J Ralph
- Department of Urology, University College London, London, UK
| | - Selim Cellek
- Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK
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Venetsanaki V, Polyzos SA. Menopause and Non-Alcoholic Fatty Liver Disease: A Review Focusing on Therapeutic Perspectives. Curr Vasc Pharmacol 2020; 17:546-555. [PMID: 29992886 DOI: 10.2174/1570161116666180711121949] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 06/05/2018] [Accepted: 06/14/2018] [Indexed: 02/06/2023]
Abstract
There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives.
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Affiliation(s)
- Vasiliki Venetsanaki
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Radhakrishnan S, Ke JY, Pellizzon MA. Targeted Nutrient Modifications in Purified Diets Differentially Affect Nonalcoholic Fatty Liver Disease and Metabolic Disease Development in Rodent Models. Curr Dev Nutr 2020; 4:nzaa078. [PMID: 32494762 PMCID: PMC7250583 DOI: 10.1093/cdn/nzaa078] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/16/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex spectrum of disorders ranging from simple benign steatosis to more aggressive forms of nonalcoholic steatohepatitis (NASH) and fibrosis. Although not every patient with NAFLD/NASH develops liver complications, if left untreated it may eventually lead to cirrhosis and hepatocellular carcinoma. Purified diets formulated with specific nutritional components can drive the entire spectrum of NAFLD in rodent models. Although they may not perfectly replicate the clinical and histological features of human NAFLD, they provide a model to gain further understanding of disease progression in humans. Owing to the growing demand of diets for NAFLD research, and for our further understanding of how manipulation of dietary components can alter disease development, we outlined several commonly used dietary approaches for rodent models, including mice, rats, and hamsters, time frames required for disease development and whether other metabolic diseases commonly associated with NAFLD in humans occur.
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Affiliation(s)
| | - Jia-Yu Ke
- Research Diets, Inc., New Brunswick, NJ, USA
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Li H, Jia E, Hong Y, Chen Y, Jiao J. Phytoestrogens and NAFLD: Possible Mechanisms of Action. Mini Rev Med Chem 2020; 20:578-583. [PMID: 31902357 DOI: 10.2174/1389557520666200103114123] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 12/18/2018] [Accepted: 02/22/2019] [Indexed: 01/08/2023]
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) includes a variety of changes including nonalcoholic
fatty liver, cirrhosis and Hepatocellular Carcinoma (HCC), which are associated with metabolic
disorders and cardiovascular diseases. The pathogenesis of NAFLD is complex and multifactorial.
Many studies have shown that estrogen has a protective effect on premenopausal women with metabolic
disorders and non-alcoholic fatty liver disease. Estrogen supplements may, at least in theory,
prevent the development and progression of NAFLD. Phytoestrogen is extracted from plants, especially
legumes, whose molecular structure and biological activity are similar to those of mammals estrogen,
therefore it could replace the role of estrogen and prevent the occurrence of adverse reactions to
estrogen. In this article, we review the published literature related to phytoestrogens and NAFLD as
well as suggest the possible mechanisms that may underlie the association between phytoestrogens and
NAFLD.
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Affiliation(s)
- Hui Li
- Department of Dentistry, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Erna Jia
- Department of Gastroenterolgy and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yu Hong
- Department of Gastroenterolgy and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yanzhen Chen
- Department of Gastroenterolgy and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Jian Jiao
- Department of Gastroenterolgy and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, China
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15
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Potential Therapeutic Application of Estrogen in Gender Disparity of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Cells 2019; 8:cells8101259. [PMID: 31619023 PMCID: PMC6835656 DOI: 10.3390/cells8101259] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/10/2019] [Accepted: 10/12/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is hepatocyte death induced by lipotoxicity, which triggers inflammation and fibrosis, leading to cirrhosis and/or liver cancer. Despite the significant burden of NAFLD, there is no therapy for NAFLD/NASH. Accumulating evidence indicates gender-related NAFLD progression. A higher incidence of NAFLD is found in men and postmenopausal women than premenopausal women, and the experimental results, showing protective actions of estradiol in liver diseases, suggest that estrogen, as the main female hormone, is associated with the progression of NAFLD/NASH. However, the mechanism explaining the functions of estrogen in NAFLD remains unclear because of the lack of reliable animal models for NASH, the imbalance between the sexes in animal experiments, and subsequent insufficient results. Herein, we reviewed the pathogenesis of NAFLD/NASH focused on gender and proposed a feasible association of estradiol with NAFLD/NASH based on the findings reported thus far. This review would help to expand our knowledge of the gender differences in NAFLD and for developing gender-based treatment strategies for NAFLD/NASH.
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Ma L, Ishigami M, Honda T, Yokoyama S, Yamamoto K, Ishizu Y, Kuzuya T, Hayashi K, Hirooka Y, Goto H. Antifibrotic Effects of 1,25(OH) 2D 3 on Nonalcoholic Steatohepatitis in Female Mice. Dig Dis Sci 2019; 64:2581-2590. [PMID: 30825110 DOI: 10.1007/s10620-019-05560-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 02/22/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. AIM We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3. METHODS Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 μg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. RESULTS Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-β, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups. CONCLUSION Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.
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Affiliation(s)
- Lingyun Ma
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
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17
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Wu B, Shah SN, Lu P, Bollinger LE, Blaeser A, Sparks S, Harper AD, Lu QL. Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 188:1069-1080. [PMID: 29571322 DOI: 10.1016/j.ajpath.2017.12.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/14/2017] [Accepted: 12/19/2017] [Indexed: 01/06/2023]
Abstract
The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.
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Affiliation(s)
- Bo Wu
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina.
| | - Sapana N Shah
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Peijuan Lu
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Lauren E Bollinger
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Anthony Blaeser
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Susan Sparks
- Clinical Genetics/Department of Pediatrics, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Amy D Harper
- Clinical Genetics/Department of Pediatrics, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina
| | - Qi L Lu
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina.
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Deng T, Liu J, Zhang M, Wang Y, Zhu G, Wang J. Inhibition effect of phytoestrogen calycosin on TGF-β1-induced hepatic stellate cell activation, proliferation, and migration via estrogen receptor β. Can J Physiol Pharmacol 2018; 96:1268-1275. [DOI: 10.1139/cjpp-2018-0474] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The present study was designed to investigate the effects of calycosin on hepatic stellate cell (HSC) function and to explore whether the drug exerts its effect through the estrogen receptor. HSC proliferation and migration were measured by MTT assay and transwell chamber assay, respectively. The mRNA and protein expression of α-SMA, COL-I, and ERβ were detected by real-time PCR and Western blotting. The co-localization and expression of α-SMA and ERβ protein were detected by immunofluorescence. All the studies were investigated in the absence or presence of ICI 182,780. The results showed that calycosin inhibited the proliferation of activated HSCs and remarkably inhibited HSC migration. Calycosin significantly reduced the expression of α-SMA and COL-I in activated HSCs. However, with co-treatment with ICI 182,780, the inhibitory effect of calycosin against the above effects was strongly negated. Importantly, calycosin significantly downregulated the expression of ERβ protein, while co-treatment with ICI 182,780 partially reversed the ERβ downregulation. In addition, α-SMA decreased with the decrease of ERβ expression and the subtype of ERβ on HSC is ERβ5. In conclusion, calycosin inhibits proliferation, activation, and migration of TGF-β1-induced HSCs. The effect may be related to binding and downregulation of ERβ5.
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Affiliation(s)
- Tan Deng
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Jing Liu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Mengmeng Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Yaxin Wang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Guannan Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Jiajia Wang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China
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Ohashi T, Kato M, Yamasaki A, Kuwano A, Suzuki H, Kohjima M, Ogawa Y. Effects of high fructose intake on liver injury progression in high fat diet induced fatty liver disease in ovariectomized female mice. Food Chem Toxicol 2018; 118:190-197. [PMID: 29751074 DOI: 10.1016/j.fct.2018.05.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 04/21/2018] [Accepted: 05/04/2018] [Indexed: 12/11/2022]
Abstract
Epidemiology shows that the morbidity of nonalcoholic fatty liver disease (NAFLD) is increased in postmenopausal women and chronic high fructose intake induces NAFLD progression. To analyze the effects of high fructose intake on estrogen deficiency, we evaluated liver disease progression using ovariectomized mice fed with a high fat diet (HFD) for 12 weeks. Hepatic steatosis developed in all HFD groups. Fructose intake significantly increased the liver weight and serum alanine aminotransferase, which was not exacerbated by ovariectomy alone. Ovariectomy enhanced the hepatic inflammatory activity shown by tumor necrosis factor α upregulation in the groups with or without fructose intake. Both fructose intake and ovariectomy increased the hepatocytes with ballooning degeneration and hepatic macrophage infiltration and activated hepatic stellate cells. Coexistence of fructose intake and ovariectomy markedly enhanced liver cell destruction, macrophage accumulation, and progression of fibrosis. Liver damage was ameliorated by 17β-estradiol supplementation. These findings suggest that high fructose intake enhanced the progression of NAFLD in ovariectomized female mice.
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Affiliation(s)
- Tomoko Ohashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Akihiro Yamasaki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akifumi Kuwano
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideo Suzuki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
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20
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Jeong YH, Hur HJ, Jeon EJ, Park SJ, Hwang JT, Lee AS, Lee KW, Sung MJ. Honokiol Improves Liver Steatosis in Ovariectomized Mice. Molecules 2018; 23:molecules23010194. [PMID: 29342107 PMCID: PMC6017725 DOI: 10.3390/molecules23010194] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 01/12/2018] [Accepted: 01/16/2018] [Indexed: 12/20/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, and is associated with the development of metabolic syndrome. Postmenopausal women with estrogen deficiency are at a higher risk of progression to NAFLD. Estrogen has a protective effect against the progression of the disease. Currently, there are no safe and effective treatments for these liver diseases in postmenopausal women. Honokiol (Ho), a bioactive natural product derived from Magnolia spp, has anti-inflammatory, anti-angiogenic, and anti-oxidative properties. In our study, we investigated the beneficial effects of Ho on NAFLD in ovariectomized (OVX) mice. We divided the mice into four groups, as follows: SHAM, OVX, OVX+β-estradiol (0.4 mg/kg of bodyweight), and OVX+Ho (50 mg/kg of diet). Mice were fed diets with/without Ho for 12 weeks. The bodyweight, epidermal fat, and weights of liver tissue were lower in the OVX group than in the other groups. Ho improved hepatic steatosis and reduced proinflammatory cytokine levels. Moreover, Ho markedly downregulated plasma lipid levels. Our results indicate that Ho ameliorated OVX-induced fatty liver and inflammation, as well as associated lipid metabolism. These findings suggest that Ho may be hepatoprotective against NAFLD in postmenopausal women.
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Affiliation(s)
- Yeon-Hui Jeong
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Haeng Jeon Hur
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Eun-Joo Jeon
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Su-Jin Park
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Jin Taek Hwang
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Ae Sin Lee
- Division of Functional Food Research, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Kyong Won Lee
- Division of Functional Food Research, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
| | - Mi Jeong Sung
- Division of Nutrition and Diet, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.
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Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats. Menopause 2017; 24:959-969. [DOI: 10.1097/gme.0000000000000864] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk. Adv Ther 2017; 34:1291-1326. [PMID: 28526997 PMCID: PMC5487879 DOI: 10.1007/s12325-017-0556-1] [Citation(s) in RCA: 392] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.
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Imai N, Suzuki M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Ishigami M, Hirooka Y, Ishikawa T, Goto H, Fujimoto T. Hepatocyte-specific depletion of ubiquitin regulatory X domain containing protein 8 accelerates fibrosis in a mouse non-alcoholic steatohepatitis model. Histochem Cell Biol 2017; 148:219-227. [PMID: 28421320 DOI: 10.1007/s00418-017-1572-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2017] [Indexed: 12/30/2022]
Abstract
Ubiquitin regulatory X domain-containing protein 8 (UBXD8) is engaged in the degradation of lipidated apolipoprotein B in hepatocytes. We previously showed that hepatocyte-specific UBXD8-deficient mice (U8-HKO) fed a moderately high-fat diet (31 kcal % fat) showed periportal macrovesicular steatosis along with a decrease in very low-density lipoprotein secretion, but did not develop fibrosis. In the present study, we examined whether U8-HKO mice show NASH-like phenotypes when fed a very high-fat diet (60 kcal % fat). U8-HKO mice and their age-matched littermates (control) were fed with two NASH model diets: choline-sufficient very high-fat diet and choline-deficient very high-fat diet. After being fed a very high-fat diet for 2 weeks, U8-HKO mice showed hepatic fibrosis in a significantly wider area than in the control. Fibrosis in U8-HKO mouse liver was further enhanced under a very high-fat diet depleted of choline (the liver surface was lumpy). Concomitant administration of an angiotensin 2 type 1 receptor blocker reduced the hepatic fibrosis caused by the very high-fat diet, suggesting the existence of inflammation. Carbon tetrachloride also induced hepatic fibrosis but the severity was comparable in the control and U8-HKO mice. In conjunction with our previous finding, the results indicate that although UBXD8 functionality can be largely compensated in the normal setting, it is crucial to sustain VLDL secretion when exposed to a dietary challenge of high fat. U8-HKO mice that develop fibrosis within 2 weeks of high-fat feeding can be used as a model to study NAFLD/NASH disease progression.
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Affiliation(s)
- Norihiro Imai
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan.
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan.
| | - Michitaka Suzuki
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Tetsuya Ishikawa
- Department of Medical Technology, Nagoya University School of Health Sciences, 1-20 Daikominami-1-chome, Higashi, Nagoya, 461-8673, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Toyoshi Fujimoto
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
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24
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Chang CC, Lee WS, Chuang CL, Hsin IF, Hsu SJ, Chang T, Huang HC, Lee FY, Lee SD. Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats. Eur J Pharmacol 2017; 802:36-43. [PMID: 28238769 DOI: 10.1016/j.ejphar.2017.02.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/22/2017] [Accepted: 02/22/2017] [Indexed: 01/13/2023]
Abstract
Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.
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Affiliation(s)
- Ching-Chih Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Wen-Shin Lee
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - I-Fang Hsin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ting Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan
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