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Yew TT, Cheah WL, Koa AJ, Chow HB. Prevalence, risk factors and association with gallstone disease of non-alcoholic fatty liver disease among rural indigenous communities: A cross-sectional study in Sarawak, Malaysia. MALAYSIAN FAMILY PHYSICIAN : THE OFFICIAL JOURNAL OF THE ACADEMY OF FAMILY PHYSICIANS OF MALAYSIA 2025; 20:8. [PMID: 40093926 PMCID: PMC11910313 DOI: 10.51866/oa.634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Introduction This study aimed to evaluate the prevalence and risk factors of non-alcoholic fatty liver disease (NAFLD) among Dayak communities in Malaysia, shedding light on an underexplored population. Methods A cross-sectional study was undertaken among Dayak villagers in Sarawak aged 18 years and above using an interview-based questionnaire, followed by an anthropometric measurement, a blood test and an abdominal ultrasound. Results A total of 324 participants met the inclusion criteria. Among them, 42.9% were men, and the mean age was 49.85±14.9 years. The prevalence of NAFLD was substantially high at 58%, with 43.1% of the participants having mild fatty liver (grade 1). NAFLD was closely associated with waist circumference and body mass index (BMI) (P<0.001). Central obesity, as indicated by waist circumference and BMI, emerged as a potent risk factor, with higher values correlating with an increased likelihood of NAFLD. A higher prevalence of NAFLD was observed in the participants with an advancing age, an elevated triglyceride level (66.7%) and a lower high-density lipoprotein cholesterol level (81.6%). However, these associations did not remain significant in the multivariate analysis. Gallstones, which share common risk factors with NAFLD, were not significantly associated with NAFLD in this population (P=0.853). Conclusion This study defines the prevalence and association of NAFLD with sociodemographic characteristics, health profiles and gallstone disease among indigenous villages in Dayak communities. A high BMI and central obesity are found to be independent risk factors of NAFLD.
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Affiliation(s)
- Ting Ting Yew
- MD, Dr.Rad, FRCR, MMed, (Diagnostic Rad), Department of Radiology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan, Sarawak, Malaysia.
| | - Whye Lian Cheah
- Phd (Community Nutrition), Department of Community Medicine & Public Health, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan, Sarawak, Malaysia
| | - Ai Jiun Koa
- MD, MMed Radiology, Department of Radiology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan, Sarawak, Malaysia
| | - Han Bing Chow
- MBBCh BAO, Msc, MRCP, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan, Sarawak, Malaysia
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La X, Zhang Z, Liang J, Li H, Pang Y, He X, Kang Y, Wu C, Li Z. Isolation and purification of flavonoids from quinoa whole grain and its inhibitory effect on lipid accumulation in nonalcoholic fatty liver disease by inhibiting the expression of CD36 and FASN. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:1330-1342. [PMID: 39305086 DOI: 10.1002/jsfa.13923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), a chronic metabolic disorder marked by excessive lipid deposition, represents a considerable health burden with no established efficacious treatment strategy. Quinoa (Chenopodium quinoa Willd.), valued for its health benefits, is replete with flavonoid bioactives. The aims of this work are to isolate and purify flavonoids from quinoa whole grain that can intervene in NAFLD and to elucidate some of the underlying mechanisms. RESULTS Chenopodium quinoa Willd. flavonoids (CQWF) were obtained successfully through an optimized ultrasonic extraction methodology, followed by isolation and purification utilizing macroporous resin D101. The study then explored the therapeutic potential of CQWF and its eluted fractions in models emulating NAFLD conditions: an in vitro fatty liver cell model induced by oleic acid (OA) and palmitic acid (PA) in the HepG2 and BEL-7402 cell lines, and an in vivo high-fat diet (HFD)-induced NAFLD model in C57BL/6N mice. The findings revealed a comprehensive mitigating effect of CQWF30 on NAFLD, manifesting in reduced intracellular lipid accumulation in steatotic hepatocytes and a concerted downregulation of key lipid metabolism genes, CD36 and FASN. Administration of CQWF30 reduced triglyceride (TG) levels in both the cellular model and the livers of HFD-fed mice. It also reduced serum concentrations of TG, total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), while increasing high-density lipoprotein cholesterol (HDL-C) in the mice. CONCLUSION These results highlighted the promising therapeutic capacity of CQWF, particularly CQWF30. This research advances the exploration and utilization of flavonoids derived from quinoa whole grain, providing innovative dietary intervention strategies for NAFLD. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Xiaoqin La
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Shanxi University, Taiyuan, China
| | - Zhaoyan Zhang
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Jingyi Liang
- Institute of Biotechnology, Shanxi University, Taiyuan, China
| | - Hanqing Li
- School of Life Science, Shanxi University, Taiyuan, China
| | - Yan Pang
- School of Life Science, Shanxi University, Taiyuan, China
| | - Xiaoting He
- School of Life Science, Shanxi University, Taiyuan, China
| | - Yurui Kang
- School of Life Science, Shanxi University, Taiyuan, China
| | - Changxin Wu
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Zhuoyu Li
- Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Shanxi University, Taiyuan, China
- Institute of Biotechnology, Shanxi University, Taiyuan, China
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Mohamed AS, Ahmad HM, Sharawy MA, Kamel FMM. The effect of vildagliptin versus metformin on hepatic steatosis in type 2 diabetic patients: a randomized controlled trial. BMC Pharmacol Toxicol 2024; 25:94. [PMID: 39673064 PMCID: PMC11645785 DOI: 10.1186/s40360-024-00818-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/20/2024] [Indexed: 12/15/2024] Open
Abstract
BACKGROUND The risk of hepatic steatosis (HS) is elevated in patients with type 2 diabetes mellitus (T2D). Antidiabetic medications may contribute to the prevention or treatment of HS. This study aimed to compare the effects of vildagliptin and metformin on hepatic steatosis in newly diagnosed T2D patients, using the Hepatic Steatosis Index (HSI) and ultrasound grading. METHODS The study included 246 newly diagnosed T2D patients who were randomly assigned to two groups. The first group (117 patients) received 50 mg of vildagliptin orally twice daily. The second group (129 patients) received 500 mg of metformin orally twice daily with meals, and the dosage could be gradually increased by 500 mg per week, up to a maximum daily dose of 2000 mg. Baseline and 6-month follow-up assessments included fasting blood glucose (FBG), HbA1c, weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), the Hepatic Steatosis Index (HSI), and hepatic steatosis grading via ultrasound. RESULTS Both groups showed significant improvements in FBG, HbA1c, weight, BMI, WC, HC, HSI, and ultrasound grading of hepatic steatosis from baseline to the 6-month follow-up (p < 0.001). The metformin group demonstrated significantly greater reductions in weight and BMI compared to the vildagliptin group (p = 0.001 and p = 0.009, respectively). However, there was no significant difference between the two groups in terms of hepatic steatosis improvement on ultrasound. Correlation analysis revealed that HSI was significantly associated with HbA1c, BMI, WC, and HC (p < 0.001 for all), as well as FBG (p = 0.008), but not with age. The lipid profile, particularly total cholesterol and LDL, was identified as a stronger predictor of hepatic steatosis, based on high AUC, sensitivity, and specificity values. CONCLUSION Both vildagliptin and metformin are effective in improving glycemic control in newly diagnosed T2D patients, as evidenced by reductions in FBG and HbA1c levels. Additionally, both drugs significantly reduced the HSI, body weight, and BMI, with metformin showing a more pronounced effect on weight and BMI. Both vildagliptin and metformin effectively decreased hepatic steatosis in T2D patients. Total cholesterol and LDL are important predictors of hepatic steatosis. TRIAL REGISTRATION Trial Registration ID: UMIN000055121, registered on 30/07/2024 (retrospectively registered).
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Affiliation(s)
- Asmaa S Mohamed
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Port said University, Port said, Egypt.
| | - Hosam M Ahmad
- Internal Medicine and Biomedical Chemistry Departments, Egypt Ministry of Health and Population, Minia, Egypt
| | - Mohammed A Sharawy
- Internal Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt
| | - Fatma M M Kamel
- Internal Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt
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Afshari H, Noori S, Zarghi A. A novel combination of metformin and resveratrol alleviates hepatic steatosis by activating autophagy through the cAMP/AMPK/SIRT1 signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3135-3148. [PMID: 37209153 DOI: 10.1007/s00210-023-02520-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/03/2023] [Indexed: 05/22/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that is associated with the accumulation of triglycerides (TG) in hepatocytes. Resveratrol (RSV), as a natural product, and metformin have been reported to have potential lipid-lowering effects for the treatment of NAFLD via autophagy, but the combined effects of both have not yet been studied. The current study aimed to investigate the role of autophagy in the lipid-lowering effects of RSV, alone and in combination with metformin, on the hepatic steatosis model of HepG2 cells and elucidate the mechanism of action. Triglyceride measurement and real-time PCR showed that RSV-metformin reduced lipid accumulation and the expression of lipogenic genes in palmitic acid (PA)-induced HepG2 cells. Additionally, the LDH release assay indicated that this combination protected HepG2 cells against PA-induced cell death through autophagy. The western blotting analysis revealed that RSV-metformin induced autophagy by reducing the expression of p62 and increasing LC3-I and LC3-II proteins. This combination also enhanced cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels in HepG2 cells. Furthermore, SIRT1 inhibitor treatment inhibited autophagy induced by RSV-metformin, which indicated the autophagy induction is SIRT1-dependent. This study demonstrated for the first time that RSV-metformin reduced hepatic steatosis by triggering autophagy via the cAMP/AMPK/SIRT1 signaling pathway.
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Affiliation(s)
- Havva Afshari
- Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Singh A, Gainder S, Banerjee P, Goel A, Kumar P, Mondal B, Banik SP, Bagchi D. Efficacy of a Proprietary Fenugreek Seed Extract ( Trigonella foenum-graecum, Furocyst®) in Women with Polycystic Ovary Syndrome (PCOS): a Randomized, Double-Blind, Placebo-Controlled Study. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2023; 42:651-659. [PMID: 36219198 DOI: 10.1080/27697061.2022.2126410] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 06/16/2023]
Abstract
INTRODUCTION Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia, a quite common heterogenous endocrine/hormonal disorder, and accompanied by elevated androgen level, menstrual irregularity, and hirsutism. The consequences include infertility or miscarriage. It is a challenging problem to the physicians. In a one-arm, non-randomized preliminary investigation in fifty premenopausal women, we demonstrated the efficacy of Furocyst®, a patented, standardized Trigonella foenum-graecum extract, in ameliorating the symptoms of PCOS over a period of 90 consecutive days. OBJECTIVE In the present study, a double-blind, two-arm, single-center, randomized, comparative study was conducted to assess the efficacy of Furocyst® (2 capsules of 500 mg/day) in 208 pre-menopausal women diagnosed with PCOS. METHODS Ethical committee approval was obtained. A total of 208 subjects (placebo = 95; Furocyst® = 113; age:18-45 years, BMI < 42 kg/m2) completed the investigation. The comparative efficacy of placebo and Furocyst® was assessed on the number of cysts, ovarian volume, hirsutism, LH:FSH ratio, titer of TSH, SHBG, prolactin and free testosterone. Key clinical parameters such as fasting blood glucose levels, HOMA Index, cholesterol, LDL, and triglyceride levels, as well as total blood chemistry were also investigated. RESULTS Furocyst® supplementation significantly reduced the number of cysts, ovarian volume, and hirsutism levels, as well as normalized the menstrual cycle in Furocyst®-treated subjects as compared to placebo group. Furocyst® significantly reduced luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and thyroid stimulating hormone (TSH) levels, and reduced the prolactin and SHBG levels. Furocyst® significantly reduced the fasting blood glucose levels, HOMA Index, cholesterol, LDL, and triglyceride levels as compared to the placebo group, while the free testosterone levels were significantly decreased in the Furocyst® group. CONCLUSION The studies collectively demonstrated the efficacy of Furocyst® as a safe, natural phytochemical-based formulation to alleviate the symptoms of PCOS. No significant adverse events were observed.
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Affiliation(s)
- Amarjeet Singh
- Department of Community Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Panjab, India
| | - Shalini Gainder
- Department of Obstetrics & Gynecology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Panjab, India
| | - Pradipta Banerjee
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Apurva Goel
- Regulatory Department, Chemical Resources (CHERESO), Panchkula, Haryana, India
| | - Pawan Kumar
- Research and Development Department, Chemical Resources (CHERESO), Panchkula, Haryana, India
| | - Banashree Mondal
- Parkinson's Disease and Movement Disorder Program, Institute of Neurosciences, Kolkata, India
| | - Samudra P Banik
- Department of Microbiology, Maulana Azad College, Kolkata, India
| | - Debasis Bagchi
- Department of Biology, Adelphi University, Garden City, New York, USA
- Department of Pharmaceutical Sciences, Texas Southern University, Houston, Texas, USA
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Petagine L, Zariwala MG, Patel VB. Non-alcoholic fatty liver disease: Immunological mechanisms and current treatments. World J Gastroenterol 2023; 29:4831-4850. [PMID: 37701135 PMCID: PMC10494768 DOI: 10.3748/wjg.v29.i32.4831] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/14/2023] [Accepted: 08/07/2023] [Indexed: 08/25/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) causes significant global disease burden and is a leading cause of mortality. NAFLD induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of NAFLD is widely recognised, the precise triggers for disease progression are still to be fully elucidated. Furthermore, the propagation to cirrhosis is poorly understood. Whilst some progress in terms of treatment options have been explored, an incomplete understanding of the hepatic cellular and molecular alterations limits their clinical utility. We have therefore reviewed some of the key pathways responsible for the pathogenesis of NAFLD such as innate and adaptative immunity, lipotoxicity and fibrogenesis, and highlighted current trials and treatment options for NAFLD patients.
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Affiliation(s)
- Lucy Petagine
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W6UW, United Kingdom
| | - Vinood B Patel
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W6UW, United Kingdom
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Lee WH, Najjar SM, Kahn CR, Hinds TD. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism 2023; 145:155607. [PMID: 37271372 PMCID: PMC10330768 DOI: 10.1016/j.metabol.2023.155607] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/06/2023]
Abstract
Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sonia M Najjar
- Department of Biomedical Sciences and the Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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Li B, Xiao Q, Zhang J, Wang Y, Liu J, Zhang B, Liu H. Exploring the active compounds and potential mechanism of the anti-nonalcoholic fatty liver disease activity of the fraction from Schisandra chinensis fruit extract based on multi-technology integrated network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2023; 301:115769. [PMID: 36183952 DOI: 10.1016/j.jep.2022.115769] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/20/2022] [Accepted: 09/25/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis fruit is a well-known traditional Chinese medicine (TCM) that has been used to treat various liver diseases. Our previous study revealed that its extract is effective against nonalcoholic fatty liver disease (NAFLD). AIM OF THIS STUDY This study aimed to elucidate the active components and explore the underlying mechanisms of action of S. chinensis fruit in the treatment of NAFLD. MATERIALS AND METHODS A HepG2 cell model was used to screen the anti-NAFLD activity of the fraction from S. chinensis fruit extract. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to determine the components of the active fraction. Active compounds, potential targets, and key pathways were predicted for the active fraction treatment of NAFLD using network pharmacology. The anti-NAFLD effects of the active fraction and core active compound 3 were further validated using a high-fat diet (HFD)-induced NAFLD mouse model, intraperitoneal glucose tolerance test (IPGTT), and intraperitoneal insulin tolerance test (IPITT). Related hepatic mRNA expression was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to preliminarily validate the mechanism. RESULTS In vitro experiments showed that the active fraction of S. chinensis fruit ethanol (EtOH) extract was mainly concentrated in the soluble fraction of petroleum ether (PET). Thirty-seven lignans were identified in this active fraction using UPLC-Q-TOF/MS. Network pharmacology studies have indicated that its anti-NAFLD effects lie in three major active lignans (3, 24, and 27) contained in PET, which may regulate the insulin resistance signaling pathway. In vivo experiments demonstrated that PET and core active compound 3 treatment significantly attenuated hepatic steatosis and reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST), insulin, malondialdehyde (MDA), hepatic triglyceride (TG), and total cholesterol (TC) in HFD-induced mice (P < 0.05). Moreover, treatment with PET and compound 3 alleviated glucose tolerance and insulin resistance. These beneficial effects can be achieved by regulating the expression of Pik3ca, Gsk3β, Jnk1, and Tnf-α. CONCLUSION This study identified the main active fraction and compounds responsible for the anti-NAFLD activity of S. chinensis fruit. This mechanism may be related to regulation of the resistance pathway.
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Affiliation(s)
- Bin Li
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Qi Xiao
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Jianuo Zhang
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Yumeng Wang
- Animal Science and Technology College Beijing University of Agriculture, Beijing, 102206, China.
| | - Jiushi Liu
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Bengang Zhang
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Haitao Liu
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
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Afshari H, Noori S, Zarghi A. Hepatic Steatosis Alleviated by a Novel Metformin and Quercetin Combination Activating Autophagy Through the cAMP/AMPK/SIRT1 Pathway. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2023; 22:e136952. [PMID: 38116565 PMCID: PMC10728872 DOI: 10.5812/ijpr-136952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/09/2023] [Accepted: 05/28/2023] [Indexed: 12/21/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) incidence and prevalence are rapidly increasing globally. The combined effects of metformin and quercetin (Que) have yet to be investigated. However, both have demonstrated the potential to reduce triglyceride (TG) levels and treat NAFLD by promoting autophagy. The objective of the present study was to elucidate the mechanism of action and assess the role of autophagy in the lipid-lowering effects of Que, both individually and in combination with metformin, in a HepG2 cell model of hepatic steatosis. Triglyceride levels and lipogenic gene expression were reduced in HepG2 cells exposed to palmitic acid (PA) when treated with Que-metformin, as evidenced by triglyceride measurements and real-time PCR. The LDH release assay also showed that this combination induced autophagy to protect HepG2 cells from PA-induced cell death. According to the Western blot analysis outcomes, Que-metformin increased LC3-I and LC3-II protein levels while decreasing p62 expression to induce autophagy. In HepG2 cells, the co-administration of Que-metformin elevated cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels. Additionally, the inhibition of SIRT1 reversed the autophagy induced by Que-metformin. The findings of this study demonstrated for the first time that Que-metformin reduced hepatosteatosis by stimulating autophagy through the cAMP/AMPK/SIRT1 signaling pathway and diminishing inflammatory cytokines.
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Affiliation(s)
- Havva Afshari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Lactobacillus sakei MJM60958 as a Potential Probiotic Alleviated Non-Alcoholic Fatty Liver Disease in Mice Fed a High-Fat Diet by Modulating Lipid Metabolism, Inflammation, and Gut Microbiota. Int J Mol Sci 2022; 23:ijms232113436. [PMID: 36362221 PMCID: PMC9658623 DOI: 10.3390/ijms232113436] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease with a rapidly increasing number of cases worldwide. This study aimed to evaluate the effects of Lactobacillus sakei MJM60958 (MJM60958) on NAFLD in vitro and in vivo. In in vitro tests, MJM60958 significantly inhibited lipid accumulation by 46.79% in HepG2 cells stimulated with oleic acid and cholesterol (OA-C). Moreover, MJM60958 showed safe and probiotic characteristics in vitro. In the animal study, MJM60958 administration in a high-fat diet-induced NAFLD mouse model significantly reduced body weight and liver weight, and controlled aspartate aminotransferase (ALT), aspartate transaminase (AST), triglyceride (TG), urea nitrogen (BUN), and uric acid (UA) levels in the blood, which are features of NAFLD. Further, treatment with MJM60958 also reduced steatosis scores in liver tissues, serum leptin and interleukin, and increased serum adiponectin content. Moreover, administration of MJM60958 resulted in a significantly decreased expression of some genes and proteins which are related to lipid accumulation, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein 1 (SREBP-1), and also upregulated genes and protein expression of lipid oxidation such as peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1a (CPT1A). Administration of MJM60958 increased the relative abundance of specific microbial taxa such as Verrucomicrobia, which are abundant in non-NAFLD mice, and reduced Firmicutes, which are a major group in NAFLD mice. MJM60958 affected the modulation of gut microbiota and altered the strain profile of short-chain fatty acids (SCFAs) production in the cecum by reduced lactic acid and enhanced acetic acid production. Overall, MJM60958 showed potential as a probiotic that can prevent and treat NAFLD.
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Total Flavonoids from Chimonanthus nitens Oliv. Leaves Ameliorate HFD-Induced NAFLD by Regulating the Gut–Liver Axis in Mice. Foods 2022; 11:foods11142169. [PMID: 35885412 PMCID: PMC9322569 DOI: 10.3390/foods11142169] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/08/2022] [Accepted: 07/16/2022] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the chronic liver diseases with high incidence in the world. This study aimed to investigate whether total flavonoids from Chimonanthus nitens Oliv. leaves (TFC) can ameliorate NAFLD. Herein, a high-fat diet (HFD)-induced NAFLD mice model was established, and TFC was administered orally. The results showed that TFC reduced the body weight and liver index and decreased the serum and hepatic levels of triglyceride (TG) and total cholesterol (TC). TFC significantly reduced the activity of liver functional transaminase. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased by 34.61% and 39.57% in serum and 22.46% and 40.86% in the liver, respectively. TFC regulated the activities of oxidative-stress-related enzymes and upregulated the protein expression of nuclear factor E2-related factor (Nrf2)/heme oxygenase (HO-1) pathway in NAFLD mice, and the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) in serum were increased by 89.76% and 141.77%, respectively. In addition, TFC reduced the levels of free fatty acids (FFA), endotoxin (ET), and related inflammatory factors in mouse liver tissue and downregulated the expression of proteins associated with inflammatory pathways. After TFC treatment, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in the liver tissues of NAFLD mice were downregulated by 67.10%, 66.56%, and 61.45%, respectively. Finally, TFC reduced liver fat deposition, oxidative stress, and inflammatory response to repair liver damage and alleviate NAFLD. Further studies showed that TFC regulated the expression of intestinal-barrier-related genes and improved the composition of gut microbiota. Therefore, TFC reduced liver inflammation and restored intestinal homeostasis by regulating the gut–liver axis. Overall, our findings revealed a novel function of TFC as a promising prophylactic for the treatment of NAFLD.
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Huang X, Xu J, Hu Y, Huang K, Luo Y, He X. Broccoli ameliorate NAFLD by increasing lipolysis and promoting liver macrophages polarize toward M2-type. J Funct Foods 2022. [DOI: 10.1016/j.jff.2021.104898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Beta vulgaris L. (Beetroot) Methanolic Extract Prevents Hepatic Steatosis and Liver Damage in T2DM Rats by Hypoglycemic, Insulin-Sensitizing, Antioxidant Effects, and Upregulation of PPARα. BIOLOGY 2021; 10:biology10121306. [PMID: 34943221 PMCID: PMC8698622 DOI: 10.3390/biology10121306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
Simple Summary Beetroot is one of the most consumable plants across the world. Previous studies have shown many health benefits of beetroot, with evidence of having potent hypoglycemic, antioxidant, and anti-inflammatory effects. The data obtained from this study further confirmed this effect in streptozotocin-diabetic animals. They showed the ability of methanolic beetroot extract to prevent the associated hepatic oxidative stress, inflammation, steatosis, and dyslipidaemia. However, the protection mechanisms involve, at least, upregulation of endogenous antioxidants, anti-apoptotic Bcl2, and PPARα. Abstract The present study examined if methanolic beetroot extract (BE) could prevent dyslipidemia and hepatic steatosis and damage in a type-2 diabetes mellitus (T2DM) rat model and studied some mechanisms of action. T2DM was induced in adult male Wistar rats by a low single dose of streptozotocin (STZ) (35 mg/kg, i.p) and a high-fat diet (HFD) feeding for 5 weeks. Control or T2DM rats then continued on standard or HFDs for another 12 weeks and were treated with the vehicle or BE (250 or 500 mg/kg). BE, at both doses, significantly improved liver structure and reduced hepatic lipid accumulation in the livers of T2DM rats. They also reduced body weight gain, serum glucose, insulin levels, serum and hepatic levels of cholesterol, triglycerides, free fatty acids, and serum levels of low-density lipoproteins in T2DM rats. In concomitant, they significantly reduced serum levels of aspartate and alanine aminotransferases, hepatic levels of malondialdehyde, tumor-necrosis factor-α, interleukin-6, and mRNA of Bax, cleaved caspase-3, and SREBP1/2. However, both doses of BE significantly increased hepatic levels of total glutathione, superoxide dismutase, and mRNA levels of Bcl2 and PPARα in the livers of both the control and T2DM rats. All of these effects were dose-dependent and more profound with doses of 500 mg/kg. In conclusion, chronic feeding of BE to STZ/HFD-induced T2DM in rats prevents hepatic steatosis and liver damage by its hypoglycemic and insulin-sensitizing effects and its ability to upregulate antioxidants and PPARα.
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Wu D, Eeda V, Undi RB, Mann S, Stout M, Lim HY, Wang W. A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice. Mol Metab 2021; 54:101363. [PMID: 34710641 PMCID: PMC8627988 DOI: 10.1016/j.molmet.2021.101363] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/18/2021] [Accepted: 10/20/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice. METHODS A novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated. RESULTS WO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis. CONCLUSIONS WO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.
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Affiliation(s)
- Dan Wu
- Department of Medicine, Division of Endocrinology, USA
| | | | - Ram Babu Undi
- Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA
| | - Shivani Mann
- Aging & Metabolism Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Michael Stout
- Aging & Metabolism Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Hui-Ying Lim
- Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA
| | - Weidong Wang
- Department of Medicine, Division of Endocrinology, USA.
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Bhave S, Ho HK. Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease. Biomedicines 2021; 9:1776. [PMID: 34944593 PMCID: PMC8698495 DOI: 10.3390/biomedicines9121776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Recently, non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant health concern affecting approximately a quarter of the world's population. NAFLD is a spectrum of liver ailments arising from nascent lipid accumulation and leading to inflammation, fibrosis or even carcinogenesis. Despite its prevalence and severity, no targeted pharmacological intervention is approved to date. Thus, it is imperative to identify suitable drug targets critical to the development and progression of NAFLD. In this quest, a ray of hope is nestled within a group of proteins, receptor tyrosine kinases (RTKs), as targets to contain or even reverse NAFLD. RTKs control numerous vital biological processes and their selective expression and activity in specific diseases have rendered them useful as drug targets. In this review, we discuss the recent advancements in characterizing the role of RTKs in NAFLD progression and qualify their suitability as pharmacological targets. Available data suggests inhibition of Epidermal Growth Factor Receptor, AXL, Fibroblast Growth Factor Receptor 4 and Vascular Endothelial Growth Factor Receptor, and activation of cellular mesenchymal-epithelial transition factor and Fibroblast Growth Factor Receptor 1 could pave the way for novel NAFLD therapeutics. Thus, it is important to characterize these RTKs for target validation and proof-of-concept through clinical trials.
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Affiliation(s)
| | - Han Kiat Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Singapore;
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Luo P, Zheng M, Zhang R, Zhang H, Liu Y, Li W, Sun X, Yu Q, Tipoe GL, Xiao J. S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling. Acta Pharm Sin B 2021; 11:668-679. [PMID: 33777674 PMCID: PMC7982498 DOI: 10.1016/j.apsb.2020.11.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 12/18/2022] Open
Abstract
Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.
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Key Words
- ADIPOQ, adiponectin
- AKT
- ALD, alcoholic liver disease
- ALDH2, aldehyde dehydrogenase 2
- ALT, alanine aminotransferase
- AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase
- AST, aspartate aminotransferase
- ATGL, adipose triglyceride lipase
- Alcoholic liver disease
- CPT1, carnitine palmitoyltransferase I
- CYP2E1, cytochrome P450 2E1
- FDA, U.S. Food and Drug Administration
- FFA, free fatty acids
- GRB14, growth factor receptor-bound protein 14
- GSK3β
- GSK3β, glycogen synthase kinase 3 beta
- GTT, glucose tolerance test
- HSL, hormone sensitive lipase
- IGF-1, insulin-like growth factors-1
- IL, interleukin
- INSR, insulin receptor
- IRS, insulin receptor substrate
- IRS-1
- IRTK, insulin receptor tyrosine kinase
- Insulin receptor
- Insulin resistance
- LDLR, low-density lipoprotein receptor
- LRP6, low-density lipoprotein receptor related protein 6
- MTT, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide
- NAC, N-acetyl-cysteine
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NF-κB, nuclear factor kappa B
- NIAAA, National Institute on Alcohol Abuse and Alcoholism
- NRF2, nuclear factor erythroid 2-related factor 2
- ORF, open reading frame
- PA, palmitate acid
- PPARα, peroxisome proliferator-activated receptor alpha
- RER, respiratory exchange ratio
- S-Allylmercaptocysteine
- SAMC, S-allylmercaptocysteine
- SPR, surface plasmon resonance
- SREBP-1c, sterol regulatory element-binding protein 1c
- Safety
- TC, total cholesterol
- TCF/LEF, T-cell factor/lymphoid enhancer factor
- TG, triglyceride
- TNF, tumor necrosis factor
- TSA, thermal shift assay
- WAT, white adipose tissues
- WT, wild-type
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Colletta C, Colletta A, Placentino G. Lifestyle and silymarin: a fight against liver damage in NAFLD associated - prediabetic disease. J Diabetes Metab Disord 2020; 19:883-894. [PMID: 33520810 PMCID: PMC7843772 DOI: 10.1007/s40200-020-00576-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is common in both prediabetic patients and healthy overweight individuals, yet it remains understudied. This study investigates the effects of hepatic steatosis on fibrosis and evaluates the major predictors of liver injury in prediabetes and whether this damage is reversible with Mediterranean diet and administration of the nutraceutical silymarin. METHODS First, a case-control study was conducted in which 212 patients with prediabetes, not known to have NAFLD, and 126 healthy controls underwent clinical evaluation, transient elastography with measurement of liver stiffness (LS) and controlled attenuation parameter (CAP). Subsequently, the 212 prediabetic patients were enrolled into a prospective randomized interventional study: 104 were allocated to Mediterranean diet alone while 108 followed Mediterranean diet plus supplementation with silymarin (a flavonolignan complex isolated from Silybum marianum and Morus alba). The administered silymarin dose was 210 mg twice daily for 6 months. Clinical and instrumental evaluations were repeated at the end of the 6 month-study period. Prediabetics were genotyped for patatin like phospholipase domain containing 3 (PNPLA3). RESULTS In the case-control study, 29% of prediabetic patients have significant fibrosis defined as LS ≥ 7.9 kPa vs only 3% of controls (p < 0.001). PNPLA3 genotype CG/GG are significantly associated with significant fibrosis LS ≥ 7.9 relative to CC genotype χ2(1) = 76.466, p < 0.001. Binomial regression analysis shows that increase in BMI, ALT and AST are significantly associated with increased likelihood of significant fibrosis (χ2(7) = 191.9, p < .001) prior to intervention. In the randomized interventional study, prediabetics following Mediterranean diet alone (group 1) experienced a significant regression of fibrosis and decrease in ALT, HbA1c, FBS after 6 months (p < 0.001); similar findings were observed in patients following Mediterranean diet plus silymarin regimen (group 2); group 2 had a significant decrease in HbA1c relative to group 1 (95% CI: 37.8-38.6 vs 39.5-40.3, p < 0.001). CONCLUSION PNPLA3 genotype CG/GG and elevated BMI are the major predictors of significant fibrosis in prediabetic patients prior to intervention in this study. Mediterranean diet either alone or with silymarin treatment for 6 months leads to significant regression of liver damage and improvement of the glycemic profile in prediabetic patients. Yet, as combination treatment of silymarin with Mediterranean diet shows significant reduction of HbA1c when compared to diet alone, this suggests that silymarin may exert an independent anti-glycemic action.
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Affiliation(s)
- Cosimo Colletta
- Division of Internal Medicine, Hepatology COQ, Madonna del Popolo Hospital, via Lungolago Buozzi 25, 28887 Omegna, VB Italy
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Campos-Murguía A, Ruiz-Margáin A, González-Regueiro JA, Macías-Rodríguez RU. Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:5919-5943. [PMID: 33132645 PMCID: PMC7584064 DOI: 10.3748/wjg.v26.i39.5919] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 05/24/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.
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Affiliation(s)
- Alejandro Campos-Murguía
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Ricardo U Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Soliman A, De Sanctis V, Alaaraj N, Hamed N. The clinical application of metformin in children and adolescents: A short update. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:e2020086. [PMID: 32921782 PMCID: PMC7717009 DOI: 10.23750/abm.v91i3.10127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 12/25/2022]
Abstract
Metformin is a widely used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The global increase in the prevalence of obesity among children and adolescents is accompanied by the appearance and increasing prevalence of insulin resistance, prediabetes, and type 2 diabetes mellitus (T2DM). In addition, children, and adolescents with premature pubarche and polycystic ovary have considerable degree of insulin resistance. The insulin sensitizing actions of metformin encouraged many investigators and physician to use it as the key drug in these conditions for both prevention and treatment. However, long term-controlled studies are still required to assess the degree and duration of effectiveness and safety of using metformin. This review tries to update physicians about the main and the new therapeutic perspectives of this drug.
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Affiliation(s)
- Ashraf Soliman
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
| | - Vincenzo De Sanctis
- Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
| | - Nada Alaaraj
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
| | - Noor Hamed
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
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Xie K, He X, Chen K, Sakao K, Hou DX. Ameliorative effects and molecular mechanisms of vine tea on western diet-induced NAFLD. Food Funct 2020; 11:5976-5991. [PMID: 32666969 DOI: 10.1039/d0fo00795a] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease that is prevalent worldwide, and its prevention by dietary administration has recently been considered as an important strategy. In this study, we administered mice with vine tea polyphenol (VTP) extracted from Ampelopsis grossedentata, a Chinese herb, to investigate the preventive effect on western diet (WD)-induced NAFLD. Male C57BL/6N mice were fed either a normal diet (ND) or WD with or without VTP for 12 weeks. The results revealed that VTP supplementation decreased the serum levels of cholesterol and triglycerides, and reduced the accumulation of hepatic lipid droplets caused by WD. Molecular data revealed that VTP enhanced fatty acid oxidation by reactivating the WD-suppressed phosphorylation of AMP-activated protein kinaseα (AMPKα) and the expressions of peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyl transferase IA (CPT1A) and cytochrome P450, family 4, subfamily a1 (CYP4A1). VTP inhibited hepatic lipogenesis by reducing the WD-enhanced level of mature sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS). Moreover, VTP activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated expressions of hemeoxygenase-1 (HO-1) and quinone oxidoreductase (NQO1), and reduced hepatic TBARS levels to prevent hepatic oxidative stress. On the other hand, VTP also increased intestinal zonula occludens-1 (ZO-1) expression and the relative abundance of gut Akkermansia, and reduced the ratio of Firmicutes/Bacteroidetes. Thus, VTP might prevent WD-induced NAFLD by balancing fatty acid oxidation and lipogenesis, hepatic oxidative stress, and gut microbiome, at least. These results suggest that vine tea, containing a high content of the bioactive compound dihydromyricetin, is a potential food resource for preventing NAFLD.
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Affiliation(s)
- Kun Xie
- Course of Biological Science and Technology, United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan.
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SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway. Int J Mol Sci 2020; 21:ijms21124534. [PMID: 32630596 PMCID: PMC7352188 DOI: 10.3390/ijms21124534] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/11/2022] Open
Abstract
A ginsenoside F2-enhanced mixture (SGL 121) increases the content of ginsenoside F2 by biotransformation. In the present study, we investigated the effect of SGL 121 on nonalcoholic fatty liver disease (NAFLD) in vitro and in vivo. High-fat, high-carbohydrate-diet (HFHC)-fed mice were administered SGL 121 for 12 weeks to assess its effect on improving NAFLD. In HepG2 cells, SGL 121 acted as an antioxidant, a hepatoprotectant, and had an anti-lipogenic effect. In NAFLD mice, SGL 121 significantly improved body fat mass; levels of hepatic triglyceride (TG), hepatic malondialdehyde (MDA), serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In HepG2 cells, induced by oxidative stress, SGL 121 increased cytoprotection, inhibited reactive oxygen species (ROS) production, and increased antioxidant enzyme activity. SGL 121 activated the Nrf2/HO-1 signaling pathway and improved lipid accumulation induced by free fatty acids (FFA). Sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) expression was significantly reduced in NAFLD-induced liver and HepG2 cells treated with SGL 121. Moreover, SGL 121 activated adenosine monophosphate-activated protein kinase (AMPK), which plays an important role in the regulation of lipid metabolism. The effect of SGL 121 on the improvement of NAFLD seems to be related to its antioxidant effects and activation of AMPK. In conclusion, SGL 121 can be potentially used for the treatment of NAFLD.
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Ahn EM, Asamenew G, Kim HW, Lee SH, Yoo SM, Cho SM, Cha YS, Kang MS. Anti-Obesity Effects of Petasites japonicus (Meowi) Ethanol Extract on RAW 264.7 Macrophages and 3T3-L1 Adipocytes and Its Characterization of Polyphenolic Compounds. Nutrients 2020; 12:nu12051261. [PMID: 32365527 PMCID: PMC7282023 DOI: 10.3390/nu12051261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/20/2020] [Accepted: 04/26/2020] [Indexed: 01/06/2023] Open
Abstract
Koreans have been consuming Petasites Japonicus (PJ) as food. Although the therapeutic effect of PJ on allergic or inflammatory reactions associated with asthma has been proven, its effect on obesity is unclear. Therefore, the present study was aimed to assess the obesity related anti-inflammatory and anti-adipogenic effects of ethanol extract PJ (EPJ) on the inflammatory response in RAW 264.7 macrophages and on differentiation in 3T3-L1 adipocytes. In addition, the polyphenolic compound was quantitatively characterized from the EPJ using ultra performance liquid chromatography coupled with diode array detector, quadrupole time-of-flight-mass spectrometry (UPLC-DAD-QToF-MS). In RAW 264.7 or 3T3-L1, reduction of nitric oxide (in macrophages) production as well as monocyte chemoattractant protein-1 and tumor necrosis factor-α were observed. Treatment of EPJ in adipocyte differentiation showed an improvement in adiponectin and lipid accumulation and a significant reduction of PPARγ and FABP-4 mRNA expression levels. On the other hand, mRNA expression of UCP-1, PPARα, and ACO increased in the EPJ treated group. In addition, a total of 26 polyphenolic compounds were detected and of which 12 are reported for the first time from PJ. The higher content of diverse polyphenolic compounds presented in EPJ might be responsible for the observed anti-inflammatory and anti-adipogenic effect. These results suggest that PJ is valuable in improving obesity-related inflammatory responses.
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Affiliation(s)
- Eun Mi Ahn
- Department of Food Science and Human Nutrition, Jeonbuk National University, 567 Baekje-daero, Jeonju, Jeollabuk-do 54896, Korea
| | - Gelila Asamenew
- Department of Food Science and Human Nutrition, Jeonbuk National University, 567 Baekje-daero, Jeonju, Jeollabuk-do 54896, Korea
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
| | - Heon Woong Kim
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
| | - Sang Hoon Lee
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
| | - Seon-Mi Yoo
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
| | - Soo-Muk Cho
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
| | - Youn-Soo Cha
- Department of Food Science and Human Nutrition, Jeonbuk National University, 567 Baekje-daero, Jeonju, Jeollabuk-do 54896, Korea
| | - Min-Sook Kang
- Department of Agrofood Resources, Food and Nutrition Division, National Institute of Agricultural Sciences, 166 Nongsaengmyeong-ro Wanju-gun, Jeollabuk-do 55365, Korea
- Correspondence: ; Tel.: +82-63-238-3581
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Heeba GH, El-Deen RM, Abdel-Latif RG, Khalifa MMA. Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: a comparative study. Can J Physiol Pharmacol 2020; 98:498-505. [PMID: 32083947 DOI: 10.1139/cjpp-2019-0487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fats in the liver resulting in hepatic inflammation and fibrous tissue formation along with insulin resistance. This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol, or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin, and HOMA-IR (homeostasis model assessment index for insulin resistance), oxidative stress parameters, hepatic TNF-α and NF-κB gene expression, and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs. Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are needed to approve PDEIs for NAFLD treatment.
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Affiliation(s)
- Gehan H Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt
| | - Reham M El-Deen
- Ministry of Health and Population, Undersecretary preventive sector, General administration viral hepatitis, Cairo, Egypt
| | - Rania G Abdel-Latif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt
| | - Mohamed M A Khalifa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt
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Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J, Vanhaecke T, Rodrigues RM. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019; 9:E37. [PMID: 31877771 PMCID: PMC7016963 DOI: 10.3390/cells9010037] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.
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Zemel MB. Natural Products: New Hope for Nonalcoholic Steatohepatitis? J Med Food 2019; 22:1187-1188. [PMID: 31834843 DOI: 10.1089/jmf.2019.29004.mbz] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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del Carmen Baez M, Tarán M, Moya M, de la Paz Scribano Parada M. Oxidative Stress in Metabolic Syndrome: Experimental Model of Biomarkers. MODULATION OF OXIDATIVE STRESS IN HEART DISEASE 2019:313-338. [DOI: 10.1007/978-981-13-8946-7_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Clerc P, Mouzaki M, Goldman RD. Omega-3 for nonalcoholic fatty liver disease in children. CANADIAN FAMILY PHYSICIAN MEDECIN DE FAMILLE CANADIEN 2019; 65:34-38. [PMID: 30674511 PMCID: PMC6347303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Question An overweight 12-year-old male patient with nonalcoholic fatty liver disease has had little improvement in liver steatosis or triglyceride levels over the past 2 years. Is omega-3 supplementation useful in managing his condition?Answer Nonalcoholic fatty liver disease in children is prevalent in the Canadian population and can lead to liver fibrosis, cirrhosis, transplant, and reduced life expectancy. There is no recommended pharmacologic treatment of nonalcoholic fatty liver disease. Omega-3 fatty acids are associated with small improvements in liver steatosis and triglyceride concentrations. There are conflicting results with regard to liver function test results and insulin resistance, and while there might be histologic improvement revealed on biopsy, there is little evidence that fibrosis is improved. In children who have struggled to be consistent with the changes needed in their diet, particularly those with elevated triglyceride levels, there might be a role for omega-3 supplementation while continuing to focus on the mainstays of treatment (diet and physical activity); however, further research is still needed.
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Sridharan K, Sivaramakrishnan G, Sequeira RP, Elamin A. Pharmacological interventions for non-alcoholic fatty liver disease: a systematic review and network meta-analysis. Postgrad Med J 2018; 94:556-565. [PMID: 30341231 DOI: 10.1136/postgradmedj-2018-135967] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 08/28/2018] [Accepted: 09/15/2018] [Indexed: 12/14/2022]
Abstract
AIM Several drugs have been used for treating non-alcoholic fatty liver disease (NAFLD). The present study is a network meta-analysis of such drugs. DESIGN, SETTING AND PATIENTS Randomised clinical trials comparing drug interventions in patients with NAFLD were analysed. OR and weighted mean difference (95 % CI) were the effect estimates for categorical and numerical outcomes, respectively. Random-effects model was used to generate pooled estimates. Surface under the cumulative ranking curve was used to rank the treatments. MAIN OUTCOME MEASURES Proportion of responders was the primary outcome measure and non-alcoholic steatohepatitis scores, liver enzymes, lipid profile, body mass index, homeostatic model assessment of insulin resistance, intrahepatic fat and adverse events were the key secondary outcomes. RESULTS 116 studies were included in the systematic review and 106 in the meta-analysis. Elafibranor, gemfibrozil, metadoxine, obeticholic acid, pentoxifylline, pioglitazone, probiotics, telmisartan, vildagliptin and vitamin E significantly increased the response rate than standard of care. Various other drugs were observed to modify the secondary outcomes favourably. Probiotics was found with a better response in children; and elafibranor, obeticholic acid, pentoxifylline and pioglitazone in patients with type 2 diabetes mellitus. The quality of evidence observed was either low or very low. CONCLUSION In patients with NAFLD, several drugs have been shown to have variable therapeutic benefit. However, the estimates and the inferences should be considered with extreme caution as it might change with the advent of future head-to-head clinical trials.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Gowri Sivaramakrishnan
- School of Oral Health, College of Medicine, Nursing and Health Sciences, Fiji National University, Suva, Fiji
| | - Reginald Paul Sequeira
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Abdelaziz Elamin
- Department of Pediatrics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
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Chalasani N, Vuppalanchi R, Rinella M, Middleton MS, Siddiqui MS, Barritt AS, Kolterman O, Flores O, Alonso C, Iruarrizaga‐Lejarreta M, Gil‐Redondo R, Sirlin CB, Zemel MB. Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2018; 47:1639-1651. [PMID: 29696666 PMCID: PMC6001629 DOI: 10.1111/apt.14674] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 02/24/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).
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Affiliation(s)
- N. Chalasani
- Indiana University School of MedicineIndianapolisINUSA
| | | | | | | | | | | | | | | | | | | | | | - C. B. Sirlin
- University of California at San DiegoSan DiegoCAUSA
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Yan H, Gao YQ, Zhang Y, Wang H, Liu GS, Lei JY. Chlorogenic acid alleviates autophagy and insulin resistance by suppressing JNK pathway in a rat model of nonalcoholic fatty liver disease. J Biosci 2018; 43:287-294. [PMID: 29872017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases around the world and commonly associated with insulin resistance and hyperlipidemia. Chlorogenic acid (CG) was reported to have insulinsensitizing activity and exert hypocholesterolemic and hypoglycemic effect. However, the involvement of CG in NAFLD remains far from being addressed. In this study, a high-fat diet-induced NAFLD rat model was used to investigate the biological roles and underlying mechanism of CG in NAFLD. The results showed that high-fat diet-fed rats exhibited an increase in body weight, glucose tolerance, liver injury, insulin resistance, as well as autophagy and C-Jun N-terminal kinase (JNK) pathway. Nevertheless, all these effects were alleviated by CG treatment. Moreover, angiotensin treatment in CG group activated the JNK pathway, and promoted autophagy, insulin resistance, and liver injury. In conclusion, our findings demonstrated that CG ameliorated liver injury and insulin resistance by suppressing autophagy via inactivation of JNK pathway in a rat model of NAFLD. Therefore, CG might be a potential application for the treatment of NAFLD.
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Affiliation(s)
- Hua Yan
- Department of Geratology, Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710068, China
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Chlorogenic acid alleviates autophagy and insulin resistance by suppressing JNK pathway in a rat model of nonalcoholic fatty liver disease. J Biosci 2018. [DOI: 10.1007/s12038-018-9746-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Prysyazhnyuk VP, Rossokha ZI, Gorovenko NG. Variation in particular biochemical indicators, cytokine and adipokine profiles of the blood, and the structural and functional parameters of the liver in patients with nonalcoholic fatty liver disease and different genotypes by the polymorphic locus A313G of the GSTP1 gene. CYTOL GENET+ 2017; 51:455-461. [DOI: 10.3103/s0095452717060111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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da Costa GF, Santos IB, de Bem GF, Cordeiro VSC, da Costa CA, de Carvalho LCRM, Ognibene DT, Resende AC, de Moura RS. The Beneficial Effect of Anthocyanidin-Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High-Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions. Phytother Res 2017; 31:1621-1632. [PMID: 28840618 DOI: 10.1002/ptr.5898] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/25/2017] [Accepted: 07/29/2017] [Indexed: 12/25/2022]
Abstract
We hypothesized that a polyphenol-rich extract from Vitis vinifera L. grape skin (GSE) may exert beneficial effects on obesity and related metabolic disorders induced by a high-fat diet (HFD). C57/BL6 mice were fed a standard diet (10% fat, control, and GSE groups) or an HFD (60% fat, high fat (HF), and HF + GSE) with or without GSE (200 mg/kg/day) for 12 weeks. GSE prevented weight gain; dyslipidemia; insulin resistance; the alterations in plasma levels of leptin, adiponectin, and resistin; and the deregulation of leptin and adiponectin expression in adipose tissue. These beneficial effects of GSE may be related to a positive modulation of insulin signaling proteins (IR, pIRS, PI3K, pAKT), pAMPK/AMPK ratio, and GLUT4 expression in muscle and adipose tissue. In addition, GSE prevented the oxidative damage, evidenced by the restoration of antioxidant activity and decrease of malondialdehyde and carbonyl levels in muscle and adipose tissue. Finally, GSE showed an anti-inflammatory action, evidenced by the reduced plasma and adipose tissue inflammatory markers (TNF-α, IL-6). Our results suggest that GSE prevented the obesity and related metabolic disorders in HF-fed mice by regulating insulin sensitivity and GLUT4 expression as well as by preventing the oxidative stress and inflammation in skeletal muscle and adipose tissue. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Gisele França da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Izabelle Barcellos Santos
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Graziele Freitas de Bem
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Cristiane Aguiar da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Dayane Teixeira Ognibene
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Angela Castro Resende
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Roberto Soares de Moura
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
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Hussain M, Habib-Ur-Rehman, Akhtar L. Therapeutic benefits of green tea extract on various parameters in non-alcoholic fatty liver disease patients. Pak J Med Sci 2017; 33:931-936. [PMID: 29067068 PMCID: PMC5648967 DOI: 10.12669/pjms.334.12571] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 06/28/2017] [Accepted: 07/07/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND OBJECTIVE NAFLD affecting up to 30% of the population globally. Drug treatment options are limited with disappointing results. The dietary supplementation in the form of green tea is another option. Our objective was toinvestigate the effect of Green tea extract (GTE) supplementation on various parameters innon-alcoholicfatty liver disease (NAFLD) patients. METHODS This study was conducted Dept. of Medicineof Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from 15 April 2016 to 15 July 2016. Eighty overweight, non diabeticand dyslipidemic patients of NAFLD, diagnosed on the basis of ultrasound and aminotransferases level were randomized for treatmentwith capsule GTE500mg (n=40)and capsule placebo (n=40) twice a day for twelve weeks. Anthropometric parameters, liver enzymes, inflammatory markers and liver ultrasound imaging were estimated by SPSS-16 pre and post treatment. RESULTS As compared to placebo, GTE caused a significant improvement in body weight (29.5±3.8 to 27.2±3.2 kg/m2 p=0.03), BMI (86±10.5 to 80±12.4 kg p=0.026), HOMA-IR(4.32±2.25 to 3.16± 1.6 p=0.0081) lipid profile (i.e. TC: L242.5±20.5 to 215.4±18.6 mg/dl p=0.005; TG: 175±22.6 to145±18 mg/dlp=0.003; LDL-C:155±12.5 to 140±16.7 mg/dl p=0.011; HDL-C: 36.8±6.7 to46.4±5.8 mg/dl p =0.001, Aminotransferases (i.e. ALT: 70.4±15.8to52.8±12.2 IU/L p=0.04; AST: 65.8±12.4 to 44.3± 8.5U/L p =0.002) and Inflammatory markers (hs-CRP: 3.14±0.58 to 2.18±0.32 p =0.023 Adiponectin: 8.46±1.02 to 10.55±3.42μg/ml p =0.003)GTE also caused a 67.5% regression of fatty liver changes on ultrasound as compared to placebo which is 25%only. CONCLUSION GTEtherapy resulted in significant improvement in metabolic, chemical, inflammatory and radiological parameters of non-alcoholic fatty liver disease patients who were non-diabetic anddyslipidemic.
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Affiliation(s)
- Mazhar Hussain
- Dr. Mazhar Hussain, MBBS, M.Phil (Pharmacology), Department of Pharmacology & TherapeuticsSheikh Zayed Medical College, Rahim Yar Khan, Punjab, Pakistan
| | - Habib-Ur-Rehman
- Dr. Habib-Ur-Rehman, MBBS, MD, FCPS (Medicine), Department of Medicine, Sheikh Zayed Medical College & Hospital, Rahim Yar Khan, Punjab, Pakistan
| | - Lubna Akhtar
- Dr. Lubna Akhtar, MBBS, FCPS (Gynae&Obs), Department of Pharmacology & TherapeuticsSheikh Zayed Medical College, Rahim Yar Khan, Punjab, Pakistan
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Helianthus tuberosus (Jerusalem artichoke) tubers improve glucose tolerance and hepatic lipid profile in rats fed a high-fat diet. ASIAN PAC J TROP MED 2017. [PMID: 28647180 DOI: 10.1016/j.apjtm.2017.03.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVES To analyze the effects of feeding Helianthus tuberosus (HT) tubers on glucose tolerance and lipid profile in rats fed a high-fat diet (HFD). METHODS A normal HFD or HFD including 10 w/w% HT tubers (HFD + HT) was fed to F334/Jcl rats. After 10 weeks, organ weights, glucose tolerance, and lipid profile were analyzed. RESULTS The body weight, liver weight, and epidermal fat content in the HFD group were higher than those of the normal group, and similar to those of the HFD + HT group. The oral glucose tolerance test at 10 weeks revealed that the blood glucose level 30 min after beginning the test in the HFD + HT group was significantly lower than that in the HFD group. Liver triglyceride and total cholesterol levels in the HFD + HT group were significantly lower than those in the HFD group. Fecal triglyceride and total cholesterol levels in the HFD + HT group were higher than those in the HFD group. Histological analyses revealed that fat and glycogen accumulation increased in the HFD group, but decreased in the HFD + HT group. CONCLUSIONS These results indicate that HT tubers have anti-fatty liver effects based on improvements in glucose tolerance and the hepatic lipid profile.
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Santos IB, de Bem GF, Cordeiro VSC, da Costa CA, de Carvalho LCRM, da Rocha APM, da Costa GF, Ognibene DT, de Moura RS, Resende AC. Supplementation with Vitis vinifera L. skin extract improves insulin resistance and prevents hepatic lipid accumulation and steatosis in high-fat diet-fed mice. Nutr Res 2017; 43:69-81. [PMID: 28739056 DOI: 10.1016/j.nutres.2017.05.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 04/30/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is one of the most common complications of obesity. The Vitis vinifera L. grape skin extract (ACH09) is an important source of polyphenols, which are related to its antioxidant and antihyperglycemic activities. We hypothesized that ACH09 could also exert beneficial effects on metabolic disorders associated with obesity and evaluated ACH09's influence on high-fat (HF) diet-induced hepatic steatosis and insulin resistance in C57BL/6 mice. The animals were fed a standard diet (10% fat, control) or an HF diet (60% fat, HF) with or without ACH09 (200mg/[kg d]) for 12weeks. Our results showed that ACH09 reduced HF diet-induced body weight gain, prevented hepatic lipid accumulation and steatosis, and improved hyperglycemia and insulin resistance. The underlying mechanisms of these beneficial effects of ACH09 may involve the activation of hepatic insulin-signaling pathway because the expression of phosphorylated insulin receptor substrate-1, phosphatidylinositol 3-kinase, phosphorylated Akt serine/threonine kinase 1, and glucose transporter 2 was increased by ACH09 and correlated with improvement of hyperglycemia, hyperinsulinemia, and insulin resistance. ACH09 reduced the expression of the lipogenic factor sterol regulatory-element binding protein-1c in the liver and upregulated the lipolytic pathway (phosphorylated liver kinase B1/phosphorylated adenosine-monophosphate-activated protein kinase), which was associated with normal hepatic levels of triglyceride and cholesterol and prevention of steatosis. ACH09 prevented the hepatic oxidative damage in HF diet-fed mice probably by restoration of antioxidant activity. In conclusion, ACH09 protected mice from HF diet-induced obesity, insulin resistance, and hepatic steatosis. The regulation of hepatic insulin signaling pathway, lipogenesis, and oxidative stress may contribute to ACH09's protective effect.
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Affiliation(s)
- Izabelle Barcellos Santos
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Graziele Freitas de Bem
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Cristiane Aguiar da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Ana Paula Machado da Rocha
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil; Department of Physiological Sciences, Biomedical Institute, Federal University of the State of Rio de Janeiro, Brazil
| | - Gisele França da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Dayane Teixeira Ognibene
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Roberto Soares de Moura
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Angela Castro Resende
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil.
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Brandi G, De Lorenzo S, Candela M, Pantaleo MA, Bellentani S, Tovoli F, Saccoccio G, Biasco G. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis 2017; 38:231-240. [PMID: 28426878 DOI: 10.1093/carcin/bgx007] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/15/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Clearly identifiable risk factors are lacking in up to 30% of HCC patients and most of these cases are attributed to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Beyond the known risk factors for NAFLD, the intestinal microbiota, in particular dysbiosis (defined as any change in the composition of the microbiota commonly found in healthy conditions) is emerging as a new factor promoting the development of chronic liver diseases and HCC. Intestinal microbes produce a large array of bioactive molecules from mainly dietary compounds, establishing an intense microbiota-host transgenomic metabolism with a major impact on physiological and pathological conditions. A better knowledge of these 'new' pathways could help unravel the pathogenesis of HCC in NAFLD to devise new prevention strategies. Currently unsettled issues include the relative role of a 'negative microbiota' (in addition to the other known risk factors for NASH) and the putative prevention of NAFLD through modulation of the gut microbiota.
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Affiliation(s)
- Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
| | - Marco Candela
- Department of Pharmacy and Biotechnology, Bologna University, via Belmeloro 6, 40126 Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
| | - Stefano Bellentani
- Department of Gastroenterology and Hepatology, Centre Point Clinic, 24e Little Russell Street, Holborn, London WC1A 2HS, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | | | - Guido Biasco
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
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Hussain M, Majeed Babar MZ, Hussain MS, Akhtar L. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. Pak J Med Sci 2016; 32:1396-1401. [PMID: 28083033 PMCID: PMC5216289 DOI: 10.12669/pjms.326.11133] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective: To determine the effect of Vildagliptin in non-alcoholic, fatty liver disease patients with dyslipidemia. Methods: A randomized placebo controlled trial was conducted at outpatient clinic of Medical Unit-I of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which fifty eight patients of NAFLD with dyslipidemia were divided in to two, case and control groups. The case group was given tablet Vildagliptin 50mg twice a day for twelve weeks and control group was given placebo in same way. Body weight, body mass index (BMI), lipid profile, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. Results: After 12 weeks treatment of vildagliptin there was significant improvement in following parameters. Body weight and BMI decreased significantly from 88 ± 11 to79 ± 12 kg (p0.036) and 30±4to 27±5 kg/m2 (p 0.005) respectively. Notable reduction in the value of TC, TG and LDL-C (TC:252±24 to 220±20mg/dl (p 0.031); TG: 190±24 to115±22 mg/dl (p 0.005); LDL-C 160±15 to 145±13mg/dl (p 0.004). HDL-C level increased significantly from 29±5to45±4 mg/dl (p 0.001). There was remarkable reduction in aminotransferases level (ALT: 78± 17 to 48±14IU/L (p 0.036). AST: 63.3±13 to41±11IU/L (p 0.002). There was overall 65.5% improvement in fatty liver grading on ultrasound with vildagliptin while non significant effects were seen in placebo group in all of the above parameters. Conclusion: Vildagliptin exhibited beneficial effects in non-alcoholic fatty liver disease, Non-diabetic patients with dyslipidemia.
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Affiliation(s)
- Mazhar Hussain
- Dr. Mazhar Hussain, M.Phil-Pharmacology, Department of Pharmacology, Sheikh Zayed Medical College, Campus Police General Hospital, Jail Chowk, Rahim Yar Khan, Pakistan
| | - Muhammad Zafar Majeed Babar
- Dr. Muhammad Zafar Majeed Babar, FCPS Medicine. Department of Medicine, Medical Unit 1, Sheikh Zayed Medical College & Hospital, Rahim Yar Khan, Pakistan
| | - Muhammad Shahbaz Hussain
- Dr. Muhammad Shahbaz Hussain, M.Phil- Microbiology. Department of Pathology, Sheikh Zayed Medical College & Hospital, Rahim Yar Khan, Pakistan
| | - Lubna Akhtar
- Dr. Lubna Akhtar, FCPS Gynae & Obs, Department of Pharmacology, Sheikh Zayed Medical College, Campus Police General Hospital, Jail Chowk, Rahim Yar Khan, Pakistan
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Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: An update. Metabolism 2016; 65:1109-23. [PMID: 27237577 DOI: 10.1016/j.metabol.2016.05.003] [Citation(s) in RCA: 438] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/02/2016] [Accepted: 05/05/2016] [Indexed: 11/21/2022]
Abstract
Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered.
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Affiliation(s)
- Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK.
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Jacobs A, Warda A, Verbeek J, Cassiman D, Spincemaille P. An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present. ACTA ACUST UNITED AC 2016; 6:185-200. [DOI: 10.1002/cpmo.3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Ans Jacobs
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
| | - Anne‐Sophie Warda
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
| | - Jef Verbeek
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center Maastricht The Netherlands
| | - David Cassiman
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
- Metabolic Center, University Hospitals KU Leuven Leuven Belgium
| | - Pieter Spincemaille
- Department of Laboratory Medicine, University Hospitals KU Leuven Leuven Belgium
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Li X, Li J, Wang L, Li A, Qiu Z, Qi LW, Kou J, Liu K, Liu B, Huang F. The role of metformin and resveratrol in the prevention of hypoxia-inducible factor 1α accumulation and fibrosis in hypoxic adipose tissue. Br J Pharmacol 2016; 173:2001-15. [PMID: 27059094 DOI: 10.1111/bph.13493] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 03/11/2016] [Accepted: 03/17/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) and fibrosis in adipose tissue contribute to adipose dysfunction. This study was designed to investigate the effects of metformin and resveratrol on the regulation of HIF-1α and fibrosis in hypoxic adipose tissue. EXPERIMENTAL APPROACH Mice were fed a high-fat diet to induce hypoxia and fibrosis in adipose tissue; adipose tissue incubated in vitro in 1% O2 showed a similar change. The effects of metformin and resveratrol on hypoxia, HIF-1α accumulation, endoplasmic reticulum stress and gene expressions of extracellular matrix components and pro-inflammatory cytokines were examined. KEY RESULTS Oral administration of metformin or resveratrol prevented hypoxia and reduced HIF-1α accumulation with dephosphorylation of inositol-requiring enzyme 1α and eukaryotic initiation factor 2α, indicative of suppression of hypoxic HIF-1α activation and endoplasmic reticulum stress. Metformin and resveratrol down-regulated gene expressions of Col3α, Col6α, elastin and lysyl oxidase and thereby reduced collagen deposition in adipose tissue. The increased gene expressions of TNF-α, IL-6, monocyte chemoattractant protein 1 and F4/80 were also down-regulated by metformin and resveratrol. Metformin and resveratrol had similar effects in adipose tissue exposed to 1% O2 . Metformin reduced ATP production and prevented the reduction in oxygen tension in 3T3-L1 cells, suggesting that it prevented hypoxia by limiting oxygen consumption, whereas resveratrol reduced HIF-1α accumulation by promoting its proteasomal degradation via the regulation of AMPK/SIRT1. CONCLUSION AND IMPLICATIONS Hypoxia and fibrosis are early causes of adipose dysfunction in obesity. Both metformin and resveratrol effectively inhibited HIF-1α activation-induced fibrosis and inflammation in adipose tissue, although by different mechanisms.
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Affiliation(s)
- Xiaole Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Jia Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Lulu Wang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Aiyun Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Zhixia Qiu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Lian-Wen Qi
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Junping Kou
- State Key Laboratory of Natural Medicines, Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TMAC-CM, China Pharmaceutical University, Nanjing, China
| | - Kang Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Baolin Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Fang Huang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
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Liu G, Wen J, Guo D, Wang Z, Hu X, Tang J, Liu Z, Zhou H, Zhang W. The effects of rabeprazole on metformin pharmacokinetics and pharmacodynamics in Chinese healthy volunteers. J Pharmacol Sci 2016; 132:244-248. [PMID: 27245553 DOI: 10.1016/j.jphs.2016.04.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 03/03/2016] [Accepted: 04/12/2016] [Indexed: 12/30/2022] Open
Abstract
The aim was to investigate the role of rabeprazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of metformin. The in vitro inhibition assays on metformin transport were carried out and showed that the half maximal inhibitory concentration (IC50) of rabeprazole on OCT2-mediated metformin transport was 26.0 μM, whereas the IC50 on MATE1-mediated metformin transport inhibition was 4.6 μM. Fifteen healthy Chinese male volunteers were enrolled and given two different doses of metformin plus the co-administration of placebo or rabeprazole. Plasma concentrations of metformin were measured up to 12 h after the second dose. The glucose-lowering effects and the variation of insulin concentrations were evaluated during the oral glucose tolerance test (OGTT). The AUC0-12 of metformin plus rabeprazole were 28,276 ± 5187 ng/ml·h, which was significantly higher than AUC0-12 of metformin plus placebo (24,691 ± 3129 ng/ml·h). Thus, rabeprazole can modestly influence the PK of metformin, suggesting the precaution of using the two drugs together. In OGTTs, rabeprazole decreased the values of AUCinsulin and the maximum insulin concentration. Although rabeprazole showed inhibition effect on OCT2-mediated metformin transport, the glucose-lowering effect of metformin remained the same regardless of its PK changes. Further studies are needed to warrant the effect of rabeprazole on metformin.
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Affiliation(s)
- Guojing Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Jiagen Wen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Dong Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Zhenmin Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Xiaolei Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Jie Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China.
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García Díaz E, Guagnozzi D, Gutiérrez V, Mendoza C, Maza C, Larrañaga Y, Perdomo D, Godoy T, Taleb G. Effect of incretin therapies compared to pioglitazone and gliclazide in non-alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study. ACTA ACUST UNITED AC 2016; 63:194-201. [PMID: 26976710 DOI: 10.1016/j.endonu.2016.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 12/31/2015] [Accepted: 01/04/2016] [Indexed: 02/07/2023]
Abstract
AIM To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone. METHODS Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months. RESULTS Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28). CONCLUSIONS Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies.
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Affiliation(s)
- Eduardo García Díaz
- Unidad de Endocrinología, Hospital Dr. José Molina Orosa, Lanzarote, Canarias, España.
| | - Danila Guagnozzi
- Unidad de Gastroenterología, Hospital Vall d'Hebron, Barcelona, España
| | - Verónica Gutiérrez
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Carmen Mendoza
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Cristina Maza
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Yulene Larrañaga
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Dolores Perdomo
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Teresa Godoy
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
| | - Ghalli Taleb
- Unidad de Atención Primaria, Gerencia de Servicios Sanitarios de Lanzarote, Lanzarote, Canarias, España
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García-Heredia A, Riera-Borrull M, Fort-Gallifa I, Luciano-Mateo F, Cabré N, Hernández-Aguilera A, Joven J, Camps J. Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice. Chem Biol Interact 2016; 249:56-63. [PMID: 26945512 DOI: 10.1016/j.cbi.2016.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/23/2016] [Accepted: 03/01/2016] [Indexed: 12/11/2022]
Abstract
Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.
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Affiliation(s)
- Anabel García-Heredia
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Marta Riera-Borrull
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Isabel Fort-Gallifa
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain; Laboratori de Referència Sud, Hospital Universitari de Sant Joan, Reus, Spain
| | - Fedra Luciano-Mateo
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Noemí Cabré
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Anna Hernández-Aguilera
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Jorge Joven
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Jordi Camps
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
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Fan N, Zhang L, Xia Z, Peng L, Wang Y, Peng Y. Sex-Specific Association between Serum Uric Acid and Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Patients. J Diabetes Res 2016; 2016:3805372. [PMID: 27382573 PMCID: PMC4921134 DOI: 10.1155/2016/3805372] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/11/2016] [Accepted: 05/15/2016] [Indexed: 12/21/2022] Open
Abstract
Across-sectional study was performed in 541 type 2 diabetic patients to determine the relationship between serum uric acid (SUA) and NAFLD in type 2 diabetic patients. Clinical parameters including SUA were determined and NAFLD was diagnosed by ultrasonography. SUA was significantly higher in type 2 diabetic subjects with NAFLD than in those without NAFLD in men, but not in women. Furthermore, the prevalence rate of NAFLD increased progressively across the sex-specific SUA tertiles only in men (37.9%, 58.6%, and 72.6%, resp., P for trend < 0.001). After adjusting for confounding factors, the odd ratios (95% CI) for NAFLD were 1 (reference), 2.93 (95%CI 1.25-6.88), and 3.93 (95% CI 1.55-9.98), respectively, across the tertiles of SUA in men. Contrastingly, SUA levels in women were not independently associated with the risk of NAFLD. Our data suggests that SUA is specifically associated with NAFLD in male type 2 diabetic subjects, independent of insulin resistance and other metabolic factors.
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Affiliation(s)
- Nengguang Fan
- Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Lijuan Zhang
- Department of Endocrinology, Shanghai Songjiang Center Hospital, Shanghai 201600, China
| | - Zhenhua Xia
- Department of Endocrinology, Shanghai Songjiang Center Hospital, Shanghai 201600, China
| | - Liang Peng
- Department of Laboratory Medicine, Shanghai Songjiang Center Hospital, Shanghai 201600, China
| | - Yufan Wang
- Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yongde Peng
- Department of Endocrinology and Metabolism, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- *Yongde Peng:
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Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annu Rev Physiol 2015; 78:181-205. [PMID: 26667070 DOI: 10.1146/annurev-physiol-021115-105331] [Citation(s) in RCA: 299] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation, and hepatocyte dysfunction. Importantly, it is also closely linked to obesity and the metabolic syndrome. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma, and cardiovascular disease. Although the precise signals remain poorly understood, NAFLD pathogenesis likely involves actions of the different hepatic cell types and multiple extrahepatic signals. The complexity of this disease has been a major impediment to the development of appropriate metrics of its progression and effective therapies. Recent clinical data place increasing importance on identifying fibrosis, as it is a strong indicator of hepatic disease-related mortality. Preclinical modeling of the fibrotic process remains challenging, particularly in the contexts of obesity and the metabolic syndrome. Future studies are needed to define the molecular pathways determining the natural progression of NAFLD, including key determinants of fibrosis and disease-related outcomes. This review covers the evolving concepts of NAFLD from both human and animal studies. We discuss recent clinical and diagnostic methods assessing NAFLD diagnosis, progression, and outcomes; compare the features of genetic and dietary animal models of NAFLD; and highlight pharmacological approaches for disease treatment.
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Affiliation(s)
- Joel T Haas
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; , .,Université de Lille, F-59000 Lille, France.,INSERM UMR 1011, F-59000 Lille, France.,Institut Pasteur de Lille, F-59000 Lille, France
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Antwerp, Belgium; .,Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; , .,Université de Lille, F-59000 Lille, France.,INSERM UMR 1011, F-59000 Lille, France.,Institut Pasteur de Lille, F-59000 Lille, France
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Rahimlou M, Ahmadnia H, Hekmatdoost A. Dietary supplements and pediatric non-alcoholic fatty liver disease: Present and the future. World J Hepatol 2015; 7:2597-2602. [PMID: 26557952 PMCID: PMC4635145 DOI: 10.4254/wjh.v7.i25.2597] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 08/17/2015] [Accepted: 10/16/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. High prevalence of pediatric obesity and sedentary lifestyle has augmented the incidence of NAFLD in children. Obesity is associated with an increased risk of NAFLD through various mechanisms such as intensification of insulin resistance and increased levels of inflammatory markers. There is no approved medical intervention for treatment of pediatric NAFLD; the only proven strategy in management of pediatric NAFLD is lifestyle modification. Recently, the effects of nutritional supplements have been examined in the management of pediatric NAFLD. The purpose of this review is to summarize the studies evaluating the effects of nutritional supplements on pediatric NAFLD and explain the future direction in this field.
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Affiliation(s)
- Mehran Rahimlou
- Mehran Rahimlou, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 1948141556, Iran
| | - Hoda Ahmadnia
- Mehran Rahimlou, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 1948141556, Iran
| | - Azita Hekmatdoost
- Mehran Rahimlou, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 1948141556, Iran
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Fu L, Bruckbauer A, Li F, Cao Q, Cui X, Wu R, Shi H, Zemel MB, Xue B. Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice. Metabolism 2015; 64:1426-34. [PMID: 26303871 DOI: 10.1016/j.metabol.2015.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/18/2015] [Accepted: 07/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Leucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice. METHODS Mice were fed high leucine (24 g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50 g/kg diet) or therapeutic levels of metformin (1.5 g/kg diet; ~300 mg/kg body weight). RESULTS High-fat diet produced a 10-fold increase in inguinal fat pad weight and 25% increase in liver weight, histologically confirmed as steatosis. The leucine-metformin combinations reduced fat pad mass, normalized liver weight, liver and plasma lipids and inflammatory markers (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. Moreover, the highest sub-therapeutic levels of metformin with leucine exerted significantly greater effects than therapeutic levels of metformin and fully reversed hepatic steatosis. These effects were mediated by upregulation of hepatic AMPK and associated changes in lipogenic gene expression (fatty acid synthase, stearoyl CoA desaturase, acetyl CoA carboxylase) in the liver. CONCLUSION A low-dose leucine-metformin combination exerts comparable effects on adiposity to therapeutic doses of metformin and fully reverses hepatic steatosis in diet-induced-obese mice.
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Affiliation(s)
- Lizhi Fu
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Antje Bruckbauer
- NuSirt Biopharma Inc., 3835 Cleghorn Ave, Nashville, TN 37215, USA
| | - Fenfen Li
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Qiang Cao
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Xin Cui
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Rui Wu
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Hang Shi
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Michael B Zemel
- NuSirt Biopharma Inc., 3835 Cleghorn Ave, Nashville, TN 37215, USA
| | - Bingzhong Xue
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA.
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Hwang KA, Hwang YJ, Kim GR, Choe JS. Extracts from Aralia elata (Miq) Seem alleviate hepatosteatosis via improving hepatic insulin sensitivity. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:347. [PMID: 26438035 PMCID: PMC4595215 DOI: 10.1186/s12906-015-0871-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 09/21/2015] [Indexed: 02/07/2023]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that is strongly associated with obesity and dysregulation of insulin in the liver. However, currently no pharmacological agents have been established for the treatment of NAFLD. In this regard, we sought to evaluate the anti-NAFLD effects of Aralia elata (Miq) Seem (AE) extract and its ability to inhibit hepatic lipid accumulation and modulate cellular signaling in a high fat diet (HFD)-induced obese mouse model. Methods A model of hepatic steatosis in the HepG2 cells was induced by oleic acid. Intracellular lipid droplets were detected by Oil-Red-O staining, and the expression of sterol regulatory element-binding protein 1(SREBP-1), Fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC) 1 and 2, Peroxisome proliferator activated receptor-α (PPARα), and carnitine palmitoyl transferase 1(CPT-1) was analyzed by real time reverse transcription–Polymerase chain reaction (qRT–PCR). And glucose consumption was measured with commercial kit. Furthermore, Male C57BL/6 J mice were fed with HFD to induce NAFLD. Groups of mice were given plant extracts orally at 100 and 300 mg/kg at daily for 4 weeks. After 3 weeks of AE extract treatment, we performed oral glucose tolerance test (OGTT). Liver tissue was procured for histological examination, Phosphoinositide 3-kinase (PI3K) and Protein kinase B (PKB/Akt) activity. Results In the present study, AE extract was shown to reduce hepatic lipid accumulation and significantly downregulate the level of lipogenic genes and upregulate the expression of lipolysis genes in HepG2 cells. And also, AE extract significantly increased the glucose consumption, indicating that AE extract improved insulin resistance. Subsequently, we confirmed the inhibitory activity of AE extract on NAFLD, in vivo. Treatment with AE extract significantly decreased body weight and the fasting glucose level, alleviated hyperinsulinism and hyperlipidemia, and reduced glucose levels, as determined by OGTT. Additionally, AE extract decreased PI3K and Akt activity. Conclusions Our results suggest that treatment with AE extract ameliorated NAFLD by inhibiting insulin resistance through activation of the Akt/GLUT4 pathway. Electronic supplementary material The online version of this article (doi:10.1186/s12906-015-0871-5) contains supplementary material, which is available to authorized users.
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50
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Chen PJ, Cai SP, Huang C, Meng XM, Li J. Protein tyrosine phosphatase 1B (PTP1B): A key regulator and therapeutic target in liver diseases. Toxicology 2015; 337:10-20. [PMID: 26299811 DOI: 10.1016/j.tox.2015.08.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 08/12/2015] [Accepted: 08/15/2015] [Indexed: 12/11/2022]
Abstract
Phosphorylation of tyrosine residues within proteins, which is controlled by the reciprocal action of protein tyrosine kinases and protein tyrosine phosphatases, plays a key role in regulating almost all physiological responses. Therefore, it comes as no surprise that once the balance of tyrosine phosphorylation is disturbed, drastic effects can occur. Protein tyrosine phosphatase 1B (PTP1B), a classical non-transmembrane tyrosine phosphatase, is a pivotal regulator and promising drug target in type 2 diabetes and obesity. Recently it has received renewed attention in liver diseases and represents an intriguing opportunity as a drug target by modulating hepatocyte death and survival, hepatic lipogenesis and so on. Here, the multiple roles of PTP1B in liver diseases will be presented, with respect to liver regeneration, drug-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma.
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Affiliation(s)
- Pei-Jie Chen
- School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Shuang-Peng Cai
- School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Cheng Huang
- School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Xiao-Ming Meng
- School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Jun Li
- School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China.
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