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Wang S, Li X, Zhang B, Li Y, Chen K, Qi H, Gao M, Rong J, Liu L, Wan Y, Dong X, Yan M, Ma L, Li P, Zhao T. Tangshen formula targets the gut microbiota to treat non-alcoholic fatty liver disease in HFD mice: A 16S rRNA and non-targeted metabolomics analyses. Biomed Pharmacother 2024; 173:116405. [PMID: 38484559 DOI: 10.1016/j.biopha.2024.116405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/24/2024] [Accepted: 03/06/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Tangshen formula (TSF) has an ameliorative effect on hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD), but the role played by the gut microbiota in this process is unknown. METHOD We conducted three batches of experiments to explore the role played by the gut microbiota: TSF administration, antibiotic treatment, and fecal microbial transplantation. NAFLD mice were induced with a high-fat diet to investigate the ameliorative effects of TSF on NAFLD features and intestinal barrier function. 16S rRNA sequencing and serum untargeted metabolomics were performed to further investigate the modulatory effects of TSF on the gut microbiota and metabolic dysregulation in the body. RESULTS TSF ameliorated insulin resistance, hypercholesterolemia, lipid metabolism disorders, inflammation, and impairment of intestinal barrier function. 16S rRNA sequencing analysis revealed that TSF regulated the composition of the gut microbiota and increased the abundance of beneficial bacteria. Antibiotic treatment and fecal microbiota transplantation confirmed the importance of the gut microbiota in the treatment of NAFLD with TSF. Subsequently, untargeted metabolomics identified 172 differential metabolites due to the treatment of TSF. Functional predictions suggest that metabolisms of choline, glycerophospholipid, linoleic acid, alpha-linolenic acid, and arachidonic acid are the key metabolic pathways by which TSF ameliorates NAFLD and this may be influenced by the gut microbiota. CONCLUSION TSF treats the NAFLD phenotype by remodeling the gut microbiota and improving metabolic profile, suggesting that TSF is a functional gut microbial and metabolic modulator for the treatment of NAFLD.
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Affiliation(s)
- Shaopeng Wang
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China; College of Pharmacy, Shandong Second Medical University, Weifang, PR China
| | - Xin Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Bo Zhang
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Yuxi Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Kexu Chen
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China; College of Pharmacy, Shandong Second Medical University, Weifang, PR China
| | - Huimin Qi
- College of Pharmacy, Shandong Second Medical University, Weifang, PR China
| | - Mengqi Gao
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Jin Rong
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Lin Liu
- Zoucheng Market Supervision Administration, Jining, PR China
| | - Yuzhou Wan
- Research and Development Department, Nanjing Denovo Pharma Co., Ltd, Nanjing, PR China
| | - Xi Dong
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Meihua Yan
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Liang Ma
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China.
| | - Tingting Zhao
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, State Key Laboratory of Rsepiratory Health and Multimorbidity, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China.
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Zakariaª EM, Abdel-Ghanyª RH, Elgharbawyª AS, Alsemehᵇ AE, Metwallyª SS. A novel approach to repositioning memantine for metabolic syndrome-induced steatohepatitis: Modulation of hepatic autophagy, inflammation, and fibrosis. Life Sci 2023; 319:121509. [PMID: 36822316 DOI: 10.1016/j.lfs.2023.121509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/25/2023]
Abstract
AIMS This study investigated the possible hepatoprotective effects of memantine, compared to pioglitazone, in rat steatohepatitis, emphasizing its role in modulating hepatic autophagy. MAIN METHODS Metabolic syndrome (MetS) was provoked in adult male Wistar rats by a high fructose/fat/salt regimen for eight weeks. Then, rats were administered either memantine or pioglitazone daily for 10 weeks (both at 20 mg/kg, orally). An oral glucose tolerance test (OGTT) was done at the end of the study, and serum liver enzymes, lipids, and fasting blood glucose were measured. Also, hepatic contents of inflammatory, oxidative, and autophagy markers were quantified. Additionally, histopathological examinations of general hepatic structure and glycogen content were performed. KEY FINDINGS Compared to the MetS rats, memantine normalized fasting serum insulin, Homeostatic Model Assessment (HOMA-IR), serum lipids, and liver enzymes (ALT and AST). Memantine also markedly reduced hepatic inflammatory markers; NF-κB and TNF-α. In addition, hepatic NRF2 and GSH were augmented, while hepatic MDA was reduced by memantine. Interestingly, livers of the memantine group showed elevated Beclin1 and LC3 and reduced p62 contents compared to the MetS group indicating that memantine preserved hepatic autophagy. Histopathological examination revealed that memantine ameliorated hepatic steatosis and inflammation. Pioglitazone also mitigated most of the steatohepatitis-related changes, however, memantine was more effective in most of the studied parameters. SIGNIFICANCE The hepatoprotective effect of memantine against steatohepatitis is mediated, at least partly, through conserving hepatic autophagy along with anti-inflammatory, antioxidant, and anti-fibrotic effects.
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Affiliation(s)
- Esraa M Zakariaª
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
| | - Rasha H Abdel-Ghanyª
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Atef S Elgharbawyª
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amira Ebrahim Alsemehᵇ
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Sami S Metwallyª
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
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Shan Z, Nisar MF, Li M, Zhang C, Wan C(C. Theaflavin Chemistry and Its Health Benefits. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6256618. [PMID: 34804369 PMCID: PMC8601833 DOI: 10.1155/2021/6256618] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/30/2021] [Accepted: 11/02/2021] [Indexed: 02/07/2023]
Abstract
Huge epidemiological and clinical studies have confirmed that black tea is a rich source of health-promoting ingredients, such as catechins and theaflavins (TFs). Furthermore, TF derivatives mainly include theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B), and theaflavin-3,3'-digallate (TF3). All of these TFs exhibit extensive usages in pharmaceutics, foods, and traditional medication systems. Various indepth studies reported that how TFs modulates health effects in cellular and molecular mechanisms. The available literature regarding the pharmacological activities of TFs has revealed that TF3 has remarkable anti-inflammatory, antioxidant, anticancer, antiobesity, antiosteoporotic, and antimicrobial properties, thus posing significant effects on human health. The current manuscript summarizes both the chemistry and various pharmacological effects of TFs on human health, lifestyle or aging associated diseases, and populations of gut microbiota. Furthermore, the biological potential of TFs has also been focused to provide a deeper understanding of its mechanism of action.
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Affiliation(s)
- Zhiguo Shan
- College of Agriculture and Forestry, Pu'er University, Pu'er 665099, China
| | - Muhammad Farrukh Nisar
- Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang 330045, China
- Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur 63100, Pakistan
| | - Mingxi Li
- Research Center of Tea and Tea Culture, College of Agronomy, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Chunhua Zhang
- College of Agriculture and Forestry, Pu'er University, Pu'er 665099, China
| | - Chunpeng (Craig) Wan
- Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang 330045, China
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Deenin W, Malakul W, Boonsong T, Phoungpetchara I, Tunsophon S. Papaya improves non-alcoholic fatty liver disease in obese rats by attenuating oxidative stress, inflammation and lipogenic gene expression. World J Hepatol 2021; 13:315-327. [PMID: 33815675 PMCID: PMC8006076 DOI: 10.4254/wjh.v13.i3.315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/30/2020] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a global health issue that is correlated with obesity and oxidative stress.
AIM To evaluate the anti-NAFLD effect of papaya in high fat diet induced obesity in rats.
METHODS Four-week-old male Sprague-Dawley rats were divided into four groups after 1 wk of acclimatization: Group 1 was the rats fed a normal diet (C); group 2 was the rats fed a high fat diet (HFD); group 3 was the rats fed a HFD with 0.5 mL of papaya juice/100 g body weight (HFL), and group 4 was the rats fed a HFD with 1 mL of papaya juice/100 g body weight (HFH) for 12 wk. At the end of the treatment, blood and tissue samples were collected for biochemical analyses and histological assessment.
RESULTS The results of the HFH group showed significantly reduced body weight (HFH vs HFD, P < 0.01), decreased NAFLD score (HFH vs HFD, P < 0.05), and reduced hepatic total cholesterol (HFL vs HFD, P < 0.01; HFH vs HFD, P < 0.001), hepatic triglyceride (HFH vs HFD, P < 0.05), malondialdehyde (HFL, HFH vs HFD, P < 0.001), tumour necrosis factor-α (HFH vs HFD, P < 0.05) and interleukin-6 (HFH vs HFD, P < 0.05) when compared to the HFD group. However, the liver weight showed no significant difference among the groups. The activities of catalase and superoxide dismutase significantly increased in HFH when compared with the HFD group (P < 0.05 and P < 0.001, respectively). The suppression of transcriptional factors of hepatic lipogenesis, including sterol regulatory element-binding protein 1c and fatty acid synthase, were observed in the papaya treated group (HFH vs HFD, P < 0.05). These beneficial effects of papaya against HFD-induced NAFLD are through lowering hepatic lipid accumulation, suppressing the lipogenic pathway, improving the balance of antioxidant status, and lowering systemic inflammation.
CONCLUSION These current results provide experimental-based evidence suggesting papaya is an efficacious medicinal fruit for use in the prevention or treatment of NAFLD.
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Affiliation(s)
- Wanwisa Deenin
- Department of Physiology, Faculty of Medical Science, Naresuan University, Muang 65000, Phitsanulok, Thailand
| | - Wachirawadee Malakul
- Department of Physiology, Faculty of Medical Science, Naresuan University, Muang 65000, Phitsanulok, Thailand
| | - Tantip Boonsong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Muang 65000, Phitsanulok, Thailand
| | - Ittipon Phoungpetchara
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Muang 65000, Phitsanulok, Thailand
| | - Sakara Tunsophon
- Department of Physiology, Faculty of Medical Science, Naresuan University, Muang 65000, Phitsanulok, Thailand
- Centre of Excellence for Innovation in Chemistry, Naresuan University, Muang 65000, Phitsanulok, Thailand
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Anti-inflammatory Mechanism of Ruzu Bitters on Diet-Induced Nonalcoholic Fatty Liver Disease in Male Wistar Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:5246725. [PMID: 32774420 PMCID: PMC7395997 DOI: 10.1155/2020/5246725] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/13/2020] [Indexed: 01/17/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become notorious globally. Increasingly emerging evidence shows that NAFLD is strongly associated with inflammation, with proinflammatory cytokines such as interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) playing a vital role in its progression. In this work, an attempt was made to verify the anti-inflammatory activity of Ruzu herbal bitters (RHB), an antiobesity medicinal concoction, on NAFLD induced by a high-fat diet (HFD) in albino Wistar rats. Twenty-five (25) rats were divided into five groups as follows: Group 1, the normal control, was maintained on standard rat chow and received normal saline (1 ml/kg body weight (BW)/day) for twelve weeks. The other groups were maintained on HFD for twelve weeks. Thereafter, groups 2–5 were treated with pioglitazone (4 mg/kg BW/day), RHB (0.6 ml/kg BW/day), normal saline (1 ml/kg BW/day), and fenofibrate (10 mg/kg BW/day), respectively. The animals were sacrificed after the experimental period. Biochemical indicators of oxidative stress and inflammation were assayed in the liver according to standard methods. The histological features of the liver were also compared to assess liver damage. RHB significantly (p < 0.05) reduced body weight and liver index, inhibited oxidative stress, boosted antioxidant enzymes by increasing the activity and level of SOD and GSH, reduced proinflammatory markers (IL-2, IL-6, TNF-α), and reversed histological alterations induced by NAFLD in rat liver. In conclusion, the anti-inflammatory activity of RHB in the prevention of NAFLD in rats has been confirmed.
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Farag M, Ashour E, El-Hadidy W. Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats. DUBAI MEDICAL JOURNAL 2020. [DOI: 10.1159/000506899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: The use of high-fructose (Fr) corn sweeteners and sucrose in manufactured food has markedly increased recently. This excessive Fr intake has been proposed in the etiology of the metabolic syndrome, which shows an increasing prevalence throughout the world. Objective: In this study, we questioned whether fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR)-α agonist, and pioglitazone (PG), a PPAR-γ agonist, might be effective in ameliorating the metabolic syndrome in a rat model. Materials and Methods: The metabolic syndrome was induced by feeding rats a high-Fr (60%) diet for 10 weeks. The rats were divided into 5 groups: control group, fed a normal rat chow; Fr + vehicle group; Fr + FF group; Fr + PG group; and Fr + (FF + PG) group (treated with both drugs). Drug or vehicle treatment was given daily for 6 weeks (from weeks 5 to 10). Thereafter, blood and liver samples were obtained for biochemical studies. Results: Rats fed a high-Fr diet developed hyperglycemia, hyperinsulinemia, hyperuricemia, hypertriglyceridemia, and hypercholesterolemia, and had increased serum alanine aminotransferase, hepatic tumor necrosis factor-α, and malondialdehyde levels but decreases in both glutathione content and superoxide dismutase activity. Rat treatment with FF and/or PG attenuated these alterations. The improvement was greater with the combined treatment than with either drug alone, and normalization of insulin sensitivity was observed only in rats treated with the combination therapy. Conclusion: Acting on the 2 main PPAR subfamilies, the combination of FF and PG provides a more efficacious therapy for modulating the changes in serum insulin, uric acid, and lipids, as well as the accompanying hepatic inflammation and oxidative stress that characterize the Fr-induced metabolic syndrome.
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Zhang W, An R, Li Q, Sun L, Lai X, Chen R, Li D, Sun S. Theaflavin TF3 Relieves Hepatocyte Lipid Deposition through Activating an AMPK Signaling Pathway by targeting Plasma Kallikrein. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:2673-2683. [PMID: 32050765 DOI: 10.1021/acs.jafc.0c00148] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of chronic liver diseases throughout the world. The deficit of pharmacotherapy for NAFLD calls for an urgent need for a new drug discovery and lifestyle management. Black tea is the most popular and functional drink consumed worldwide. Its main bioactive constituent theaflavin helps to prevent obesity-a major risk factor for NAFLD. To find new targets for the development of effective and safe therapeutic drugs from natural plants for NAFLD, we found a theaflavin monomer theaflavin-3,3'-digallate (TF3), which significantly reduced lipid droplet accumulation in hepatocytes, and directly bound and inhibited the activation of plasma kallikrein (PK), which was further proved to stimulate adenosine monophosphate activated protein kinase (AMPK) and its downstream targets. Taken together, we proposed that the TF3-PK-AMPK regulatory axis is a novel mechanism of lipid deposition mitigation, and PK could be a new target for NAFLD treatment.
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Affiliation(s)
- Wenji Zhang
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Ran An
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China
| | - Qiuhua Li
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Lingli Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Xingfei Lai
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Ruohong Chen
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Dongli Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, P. R. China
| | - Shili Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
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Radwan RR, Hasan HF. Pioglitazone ameliorates hepatic damage in irradiated rats via regulating anti-inflammatory and antifibrogenic signalling pathways. Free Radic Res 2019; 53:748-757. [PMID: 31146611 DOI: 10.1080/10715762.2019.1624742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatic irradiation during radiotherapy is associated with liver damage. The current study was designed to investigate the possible modulatory effects of pioglitazone against γ irradiation-induced hepatic damage in rats. Animals were exposed to a single dose of 6 Gy and received pioglitazone (10 mg/kg/day) orally for 4 weeks starting on the same day of irradiation. Results showed that irradiation increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as serum triglyceride (TG) and total cholesterol (TC) levels. Furthermore, it elevated inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6); nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) in hepatic tissues. Moreover, it increased levels of serum fibrotic markers; hyaluronic acid (HA), laminin (LN), and type III procollagen (PCIII). Additionally, hepatic fibrotic markers; transforming growth factor-β1 (TGF-β1) and hydroxyproline (HP) levels were elevated. Histological analysis of H&E and MT staining of liver sections exhibited cellular infiltration and fibrous deposition in irradiated rats. It was observed that pioglitazone modulated the described deviations. In conclusion, pioglitazone could serve as a promising therapeutic tool for attenuating radiation-induced liver injury in patients with radiotherapy which might be attributed to its anti-inflammatory and antifibrotic activities.
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Affiliation(s)
- Rasha R Radwan
- a Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA) , Nasr City , Egypt
| | - Hesham F Hasan
- b Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy Authority , Cairo , Egypt
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Karimi-Sales E, Ebrahimi-Kalan A, Alipour MR. Preventive effect of trans-chalcone on non-alcoholic steatohepatitis: Improvement of hepatic lipid metabolism. Biomed Pharmacother 2018; 109:1306-1312. [PMID: 30551380 DOI: 10.1016/j.biopha.2018.10.196] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/25/2018] [Accepted: 10/31/2018] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is an inflammatory and progressive form of non-alcoholic fatty liver disease. However, there are no FDA-approved drugs for this condition. Lipids accumulated in NASH have a direct role in the progression of this disease. Therefore, this study for the first time explored the preventive effect of trans-chalcone on NASH through the modulation of sterol regulatory element binding protein (SREBP)-1c, SREBP-2, hepatic fatty acid synthesis (FAS) enzyme, proliferator-activated receptor (PPAR)-α, and PPAR-γ2 levels, which are involved in hepatic lipid metabolism. In this study, male rats were randomly divided into three groups (n = 7): Control, received 10% tween 80; NASH, received 10% tween 80 and 10 ml/kg high-fat emulsion (high-fat diet, HFD); and NASH + TC, received 20 mg/kg trans-chalcone and 10 ml/kg HFD. All treatments were performed by once-daily oral gavage for 6 weeks. Liver and blood samples were collected and serum levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and high-density lipoprotein (HDL)-cholesterol, as well as hepatic levels of SREBP-1c, SREBP-2, FAS, PPAR-α, and PPAR-γ2, were measured. Moreover, hematoxylin and eosin stained tissues were used for histological analysis. In this study, treatment of HFD-fed rats with trans-chalcone significantly reduced abnormalities in liver histology, serum levels of liver injury markers, liver index, and hepatic levels of SREBP-1c, SREBP-2, FAS, and PPAR-γ2. Furthermore, trans-chalcone significantly increased hepatic PPARα levels in these rats. Therefore, it seems that trans-chalcone protects the liver of HFD-fed rats against NASH development through reduction of SREBP-1c/ FAS- and PPAR-γ2-related lipogenesis, attenuation of SREBP-2-related cholesterol synthesis, and elevation of PPARα-related fatty acid oxidation.
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Affiliation(s)
- Elham Karimi-Sales
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi-Kalan
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Al-Muzafar HM, Amin KA. Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl-CoA desaturase-1, lipase activity, leptin and resistin. Exp Ther Med 2018; 16:2938-2948. [PMID: 30214514 PMCID: PMC6125847 DOI: 10.3892/etm.2018.6563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 04/06/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80-90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13-16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.
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Affiliation(s)
- Hessah Mohammed Al-Muzafar
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Kamal Adel Amin
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
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Li D, Zheng J, Hu Y, Hou H, Hao S, Liu N, Wang Y. Amelioration of Intestinal Barrier Dysfunction by Berberine in the Treatment of Nonalcoholic Fatty Liver Disease in Rats. Pharmacogn Mag 2017; 13:677-682. [PMID: 29200733 PMCID: PMC5701411 DOI: 10.4103/pm.pm_584_16] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/01/2017] [Indexed: 12/20/2022] Open
Abstract
Objective: To investigate the effect of berberine (BBR) on intestinal barrier function in nonalcoholic fat liver disease (NAFLD) in rats. Materials and Methods: Rats were divided into three groups: normal diet group (control group [CON group]), high-fat diet feeding group (HFD group), and HFD with BBR group. After 8 weeks of HFD feeding, rats in the BBR group were given BBR intragastrically at a dose of 150 mg/kg daily for 4 weeks. The same volume of normal saline was given to the CON and HFD groups. Liver index was detected, and Sudan black B staining was used to study fatty degeneration, also the expression level of occluding and intestinal flora was analyzed. Results: BBR administration significantly reduced HFD-induced increase in body weight (CON group: 379.83 ± 61.51 g, HFD group: 485.24 ± 50.15 g, and BBR group: 428.60 ± 37.37 g). It obviously alleviated the HFD-induced liver fatty degeneration and histopathological changes of intestinal mucosa according to liver index low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and total cholesterol (P < 0.05). The triglyceride, alanine transaminase, and aspartate aminotransferase levels were greatly elevated after BBR treatment (P < 0.05); while endotoxin, intestinal fatty acid-binding protein, and tumor necrosis factor-α were significantly reduced (P < 0.05). Moreover, we found that BBR could obviously elevate the level of occludin and decrease the level of Faecalibacterium prausnitzii and upregulate the level of bacteroides. Conclusion: BBR provides significant protection in NAFLD through ameliorating intestinal barrier function. SUMMARY
Berberine (BBR), an alkaloid that can be isolated from many plants, has been medically used for its wide range of antimicrobial and anti-inflammatory effects This is a study of BBR on liver function and intestinal barrier function in nonalcoholic fat liver disease (NAFLD) BBR treatment for NAFLD could significantly restore the liver function and provide significant protection in NAFLD through ameliorating intestinal barrier function.
Abbreviations used: BBR: Berberine, NAFLD: Nonalcoholic fat liver disease, ALT: Alanine transaminase, AST: Aspartate aminotransferase, TG: Triglyceride, I-FABP: Intestinal-fatty acid-binding protein, IBD: Inflammatory bowel disease.
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Affiliation(s)
- Donghao Li
- Department of Gastroenterology, Affiliated Hospital of Hebei University of Engineering, Handan 056038, China
| | - Jimin Zheng
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050051, China
| | - Yiting Hu
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050051, China
| | - Hongtao Hou
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050051, China
| | - Shurong Hao
- Department of Infectious Diseases, Handan County Hospital, Handan 056001, China
| | - Na Liu
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050051, China
| | - Yuzhen Wang
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050051, China
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Haiyan W, Linyi L, Lingling Q, Dongchao W, Yueying J, Xinli W, Tunhai X, Tonghua L. Mixture of five herbal extracts ameliorates pioglitazone-induced aggravation of hepatic steatosis via activating the adiponectin receptor 2/AMP-activated protein kinase signal pathway in diabetic KKAy mice. J TRADIT CHIN MED 2017. [DOI: 10.1016/s0254-6272(17)30311-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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13
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Al Zarzour RH, Ahmad M, Asmawi MZ, Kaur G, Saeed MAA, Al-Mansoub MA, Saghir SAM, Usman NS, Al-Dulaimi DW, Yam MF. Phyllanthus Niruri Standardized Extract Alleviates the Progression of Non-Alcoholic Fatty Liver Disease and Decreases Atherosclerotic Risk in Sprague-Dawley Rats. Nutrients 2017; 9:E766. [PMID: 28718838 PMCID: PMC5537880 DOI: 10.3390/nu9070766] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/19/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri (P. niruri). NAFLD was induced in male Sprague-Dawley rats using a special high-fat diet (HFD). A 50% methanolic extract (50% ME) exhibited the highest inhibitory effect against NAFLD progression. It significantly reduced hepatomegaly (16%) and visceral fat weight (22%), decreased NAFLD score, prevented fibrosis, and reduced serum total cholesterol (TC) (48%), low-density lipoprotein (LDL) (65%), free fatty acids (FFAs) (25%), alanine aminotransferase (ALT) (45%), alkaline phosphatase (ALP) (38%), insulin concentration (67%), homeostatic model assessment of insulin resistance (HOMA-IR) (73%), serum atherogenic ratios TC/high-density lipoprotein (HDL) (29%), LDL/HDL (66%) and (TC-HDL)/HDL (64%), hepatic content of cholesterol (43%), triglyceride (29%) and malondialdehyde (MDA) (40%) compared to a non-treated HFD group. In vitro, 50% ME of P. niruri inhibited α-glucosidase, pancreatic lipase enzymes and cholesterol micellization. It also had higher total phenolic and total flavonoid contents compared to other extracts. Ellagic acid and phyllanthin were identified as major compounds. These results suggest that P. niruri could be further developed as a novel natural hepatoprotective agent against NAFLD and atherosclerosis.
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Affiliation(s)
- Raghdaa Hamdan Al Zarzour
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Mariam Ahmad
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Mohd Zaini Asmawi
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Gurjeet Kaur
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Mohammed Ali Ahmed Saeed
- Discipline of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Majed Ahmed Al-Mansoub
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Sultan Ayesh Mohammed Saghir
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Nasiba Salisu Usman
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Dhamraa W Al-Dulaimi
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Mun Fei Yam
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
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Azeemuddin M, Rafiq M, Anturlikar SD, Sharath Kumar LM, Patki PS, Babu UV, Shyam R. Extract of a polyherbal formulation ameliorates experimental nonalcoholic steatohepatitis. J Tradit Complement Med 2016; 6:160-7. [PMID: 27114939 PMCID: PMC4833463 DOI: 10.1016/j.jtcme.2014.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/24/2014] [Accepted: 12/04/2014] [Indexed: 12/16/2022] Open
Abstract
The objective of the present study is to evaluate the effect of the extract of a well-known hepatospecific polyherbal formulation, Liv.52, in an experimental model of high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats. Feeding a HFD for 15 weeks resulted in significant impairment of the lipid profile, elevation of hepatic enzyme markers, and insulin resistance in rats. The histological examination of the liver furthermore indicated fibrotic changes and fat deposition in hepatic tissues. The treatment with Liv.52 extract [125 mg/kg body weight per os (b.wt. p.o.)], which was administered from week 9 onward, reversed the HFD-induced changes to a statistically significant extent, compared to the untreated positive control animals. The effect observed with Liv.52 extract was comparable to that of pioglitazone (4 mg/kg b.wt.), a standard drug that is useful in the management of NASH. The treatment with Liv.52 extract significantly reduced steatosis, collagen deposition, and necrosis in hepatic tissues, which indicates its antifibrotic and antinecrotic properties. The results obtained in the present set of experiments indicate that Liv.52 extract effectively reverses metabolic and histological changes associated with HFD-induced NASH.
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Affiliation(s)
- Mohammed Azeemuddin
- Department of Pharmacology, R&D Center, The Himalaya Drug Company, Bangalore, India
| | - Mohamed Rafiq
- Department of Pharmacology, R&D Center, The Himalaya Drug Company, Bangalore, India
| | | | | | | | | | - Ramakrishnan Shyam
- Chief Scientific Officer, R&D Center, The Himalaya Drug Company, Bangalore, India
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15
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Abd El-Haleim EA, Bahgat AK, Saleh S. Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression. Eur J Pharmacol 2016; 773:59-70. [PMID: 26825546 DOI: 10.1016/j.ejphar.2016.01.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 02/09/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions.
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Affiliation(s)
- Enas A Abd El-Haleim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Ashraf K Bahgat
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Samira Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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16
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Protective effect of boswellic acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: influence on insulin resistance and energy expenditure. Naunyn Schmiedebergs Arch Pharmacol 2015; 388:587-600. [PMID: 25708949 DOI: 10.1007/s00210-015-1102-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 02/03/2015] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.
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Elshazly SM. Ameliorative effect of nicorandil on high fat diet induced non-alcoholic fatty liver disease in rats. Eur J Pharmacol 2015; 748:123-32. [DOI: 10.1016/j.ejphar.2014.12.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 12/12/2014] [Accepted: 12/15/2014] [Indexed: 02/07/2023]
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Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070-18091. [PMID: 25561778 PMCID: PMC4277948 DOI: 10.3748/wjg.v20.i48.18070] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/21/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
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19
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Tzanetakou IP, Doulamis IP, Korou LM, Agrogiannis G, Vlachos IS, Pantopoulou A, Mikhailidis DP, Patsouris E, Vlachos I, Perrea DN. Water Soluble Vitamin E Administration in Wistar Rats with Non-alcoholic Fatty Liver Disease. Open Cardiovasc Med J 2012; 6:88-97. [PMID: 22930662 PMCID: PMC3428633 DOI: 10.2174/1874192401206010088] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 07/15/2012] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE A diet rich in fat is associated with hepatic fat deposition [steatosis; non-alcoholic fatty liver disease (NAFLD)]. The exact cause of NAFLD however, is still unknown. The aim of this study was to assess the effect of a water-soluble formulation of vitamin E on a dietary-induced-NAFLD animal model. METHODS Adult male Wistar rats (n=20) were allocated to 2 groups: Controls (Group A, n=6), which received a standard chow diet for 24 weeks and a High Cholesterol group (HC: n=14), which received a standard chow diet enriched with cholesterol for the first 14 weeks of the experiment (t(1)). At t(1), the HC group was divided into: Group HC(B), which received a high-saturated-fat/high-cholesterol (HSF/HCH) diet and Group HC(C), which followed the same HSF/HCH diet but was also administered water soluble vitamin E (10 IU/kg body weight/day), for 10 more weeks. RESULTS At the end of the study, group HC(C) exhibited significantly lower mean total cholesterol (T-CHOL) than group HC(B) (p<0.001). No significant differences were observed between HC(C) and Control groups in blood glucose and serum lipid concentrations. Liver Function Tests did not vary between all groups at the end of the study. Animals in group HC(B) exhibited higher SGOT at the end of the study compared with the beginning of the study (p<0.05). Group HC(B) exhibited the highest scores in steatosis, and grading (according to the NAFLD scoring system) in the histopathological analysis (p≤0.001 in all cases). CONCLUSIONS Vitamin E seems to exert a hypolipidemic and hepatoprotective role in the presence of a HSF/HCH atherogenic diet in a rat model.
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Affiliation(s)
- Irene P Tzanetakou
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - Ilias P Doulamis
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - Laskarina-Maria Korou
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - George Agrogiannis
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis S Vlachos
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - Alkisti Pantopoulou
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK
| | - Efstratios Patsouris
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Vlachos
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
| | - Despina N Perrea
- Laboratory for Experimental Surgery and Surgical Research “N. S. Christeas”, University of Athens Medical School, Athens, Greece
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20
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Schaalan MF. Effects of pioglitazone and/or simvastatin on circulating TNFα and adiponectin levels in insulin resistance. J Immunotoxicol 2012; 9:201-9. [DOI: 10.3109/1547691x.2012.660998] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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21
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Wu XQ, Kong X, Zhou Y, Huang K, Yang JR, Li XL. Sesamin exerts renoprotective effects by enhancing NO bioactivity in renovascular hypertensive rats fed with high-fat-sucrose diet. Eur J Pharmacol 2012; 683:231-7. [PMID: 22314221 DOI: 10.1016/j.ejphar.2012.01.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Revised: 01/18/2012] [Accepted: 01/21/2012] [Indexed: 11/15/2022]
Abstract
In the present study, we aimed to evaluate the protective effect of sesamin on kidney damage and renal endothelial dysfunction in two-kidney, one-clip renovascular hypertensive rats fed with a high-fat-sucrose diet (2K1C rats on HFS diet). Sesamin was intragastrically administered to 2K1C rats on HFS diet for eight weeks. Then, we measured the levels of serum hydrogen peroxide (H₂O₂), total antioxidant capability (T-AOC), renal malonaldehyde (MDA), total-erythrocuprein (T-SOD) and glutathione peroxidase (GSH-P(X)). The expressions of endothelial nitric oxide synthase (eNOS), nitrotyrosine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox) in the left and right renal cortexes were detected by Western blotting. Pathological changes in the left and right renal cortexes were observed by periodic acid-schiff staining (PAS) and Masson's staining. Treatment with sesamin (120 and 60mg/kg⁻¹·d⁻¹) in 2K1C rats on HFS diet improved renal function, corrected structural abnormalities, and attenuated renal oxidative stress. Furthermore, sesamin increased eNOS protein expression and reduced nitrotyrosine and p47phox protein expression. These results demonstrated that long-term treatment with sesamin had renoprotective effect and improved renal endothelial dysfunction via upregulation of eNOS expression and reduction of NO oxidative inactivation in both clipped and contralateral kidneys of 2K1C rats on HFS diet, and sesamin may have a favorably therapeutic value in treating chronic kidney disease in patients with hypertension and hyperlipemia.
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Affiliation(s)
- Xiang-Qi Wu
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. Eur J Pharmacol 2011; 662:70-7. [DOI: 10.1016/j.ejphar.2011.04.049] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 02/28/2011] [Accepted: 04/18/2011] [Indexed: 01/21/2023]
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Ibrahim M, Farghaly E, Gomaa W, Kelleni M, Abdelrahman AM. Nitro-aspirin is a potential therapy for non alcoholic fatty liver disease. Eur J Pharmacol 2011; 659:289-295. [PMID: 21453696 DOI: 10.1016/j.ejphar.2011.03.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 02/17/2011] [Accepted: 03/09/2011] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury; however its therapeutic strategy has not been established yet. Nitro-aspirin (NO-aspirin) is a new molecule in which aspirin and a NO-donating group are covalently linked. This study investigated the potential protective effect of NO-aspirin on NAFLD. Experimental rats were assigned into 4 groups. Group 1 was fed with normal diet and served as normal control group. Group 2 was fed with 2% cholesterol diet and received vehicle as positive control NAFLD group. Group 3 was fed with 2% cholesterol diet plus NO-aspirin (100 mg/kg/day). Group 4 was fed with 2% cholesterol diet plus aspirin (55 mg/kg/day). Rats were treated for 8 weeks. The results showed that NO-aspirin (but not aspirin) prevented the development of NAFLD as evidenced by significant reduction in liver weight/body weight ratio (liver index) and histopathologic changes. The protective effect of NO-aspirin is accompanied with significant decrease in triglycerides, malondialdehyde (MDA), and nitric oxide (NO) in hepatic tissue. Semi-quantitative immunohistochemical studies showed significant decrease in expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in hepatic tissue. In conclusion, NO-aspirin inhibited multiple pathways involved in the pathogenesis of NAFLD indicating that it might serve as a new therapeutic strategy.
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Affiliation(s)
- Mohamed Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, Egypt.
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Wang BF, Tian PY, Feng K, Wu FR, Lu YG, Yang Y. Role of insulin resistance in the pathogenesis of nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2010; 18:3175-3180. [DOI: 10.11569/wcjd.v18.i30.3175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of insulin resistance (IR) in the pathogenesis of nonalcoholic fatty liver disease in rats.
METHODS: Spraque-Dawley rats were randomly divided into normal control group and model group. The model group was fed a high-fat cholesterol-rich diet for 8 wk to induce nonalcoholic fatty liver disease and insulin resistance. The model group was further divided randomly into two equal subgroups: model control subgroup and therapeutic subgroup. Physiological saline and rosiglitazone maleate were given to the model control subgroup and therapeutic subgroup for 4 wk, respectively. Hepatic histological changes were then observed. Fasting plasma glucose, fasting insulin, plasma ApoC II and ApoC III were determined to calculate insulin resistance index. The activity of lipoprotein lipase and hepatic lipase was measured, and the expression of ApoB-100 mRNA was detected.
RESULTS: Compared with the normal control group, the body mass, fasting plasma glucose, fasting insulin and insulin resistance index were significantly higher in the model control subgroup and therapeutic subgroup (fasting plasma glucose: 6.46 mmol/L ± 0.75 mmol/L, 6.61 mmol/L ± 0.45 mmol/L vs 5.48 mmol/L ± 0.47 mmol/L; fasting insulin: 78.82 mU/L ± 11.13 mU/L, 78.48 mU/L ± 12.94 mU/L vs 40.90 mU/L ± 7.76 mU/L; insulin resistance index: 22.48 ± 2.81, 22.98 ± 3.47 vs 9.85 ± 1.15; all P < 0.05). Histological analysis revealed that the rats of the model control subgroup and therapeutic subgroup met the diagnostic criteria for fatty liver. Compared with the model control subgroup, hepatic histological changes were milder in the therapeutic subgroup. Treatment with rosiglitazone maleate significantly lowered the fasting plasma glucose (6.01 mmol/L ± 0.56 mmol/L vs 6.43 mmol/L ± 0.47 mmol/L), fasting insulin (68.11 mU/L ± 10.52 mU/L vs 82.48 mU/L ± 15.20 mU/L), insulin resistance index (18.49 ± 2.44 vs 23.39 ± 3.16) and plasma ApoC III level, but increased plasma ApoC II level and the activity of lipoprotein lipase.
CONCLUSION: Improvement of insulin resistance in fatty liver rats can improve the activity of lipoprotein lipase and hepatic lipase by altering plasma ApoC II and ApoC III levels, promote the degradation of peripheral very low-density lipoprotein and triglycerides, up-regulate hepatic expression of ApoB-100 mRNA, facilitate the synthesis of very low-density lipoprotein in the liver and the transport of endogenous triglycerides, and lessen fatty infiltration of the liver.
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Kong X, Yang JR, Guo LQ, Xiong Y, Wu XQ, Huang K, Zhou Y. Sesamin improves endothelial dysfunction in renovascular hypertensive rats fed with a high-fat, high-sucrose diet. Eur J Pharmacol 2009; 620:84-9. [PMID: 19699195 DOI: 10.1016/j.ejphar.2009.08.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2009] [Revised: 07/03/2009] [Accepted: 08/06/2009] [Indexed: 11/15/2022]
Abstract
The present study was designed to evaluate the possible in vivo protective effects of sesamin on hypertension and endothelial function in two-kidney, one-clip renovascular hypertensive rats fed with a high-fat, high-sucrose diet (2K1C rats on HFS diet). Sesamin was orally administered for 8 weeks in 2K1C rats on HFS diet. Then, the serum malondialdehyde level was determined. The protein expression of endothelial nitric oxide synthase (eNOS), nitrotyrosine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox) in aortas was detected by Western blotting. Vasorelaxation response to acetylcholine and nitroprusside, and functional assessment of nitric oxide (NO) bioactivity were also determined in aortic rings. Sesamin treatment reduced systolic blood pressure, improved vasodilatation induced by acetylcholine and enhanced NO bioactivity in the thoracic aortas. These changes were associated with increased eNOS, decreased malondialdehyde content, and reduced nitrotyrosine and p47(phox) protein expression. All these results suggest that chronic treatment with sesamin reduces hypertension and improves endothelial dysfunction through upregulation of eNOS expression and reduction of NO oxidative inactivation in 2K1C rats on HFS diet.
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Affiliation(s)
- Xiang Kong
- Department of Pharmacology, Third-Grade Pharmacology Laboratory of State Administration of Traditional Chinese Medicine, Wannan Medical College, Wuhu, Anhui Province, China
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Safwat GM, Pisanò S, D'Amore E, Borioni G, Napolitano M, Kamal AA, Ballanti P, Botham KM, Bravo E. Induction of non-alcoholic fatty liver disease and insulin resistance by feeding a high-fat diet in rats: does coenzyme Q monomethyl ether have a modulatory effect? Nutrition 2009; 25:1157-68. [PMID: 19592219 DOI: 10.1016/j.nut.2009.02.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Revised: 01/27/2009] [Accepted: 02/24/2009] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the development of non-alcoholic fatty liver disease (NAFLD) in response to a high-fat diet in rats and to test the hypothesis that dietary coenzyme Q monomethyl ether (CoQme) has antisteatogenic effects. METHODS Rats were fed a standard low-fat diet (control) for 18 wk or a diet containing 35% fat (57% metabolizable energy) for 10 wk, then divided into three groups for the following 8 wk. One group was given CoQ9me (30mg/kg body weight per day in 0.3mL olive oil: high fat+CoQ9me), the second olive oil (0.3mL/d) only (high fat + olive oil), and the third group received no supplements (high fat). RESULTS Insulin levels and the activity of alanine aminotransferase in the plasma were significantly increased in all high-fat diet groups, and the homeostasis model assessment of insulin resistance indicated insulin resistance. Triacylglycerol concentrations in whole plasma and in very low-density lipoprotein and low-density lipoprotein fractions were also raised. Liver histology showed lipid accumulation in animals fed the high-fat diets, and liver triacylglycerol levels were increased (2.5- to 3-fold) in all high-fat diet groups. These effects were not changed by the administration of CoQ9me. CONCLUSIONS Rats fed a diet with 57% energy from fat showed insulin resistance, hypertriglyceridemia, increased very low-density lipoprotein production, hepatic steatosis, and liver damage, and thus provide a good model for the early stages of NAFLD. Dietary CoQ9me, however, did not ameliorate the damaging effects of the high-fat diet.
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Affiliation(s)
- Ghada M Safwat
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy
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Wang HN, Wang YR, Liu GQ, Liu Z, Wu PX, Wei XL, Hong TP. Inhibition of hepatic interleukin-18 production by rosiglitazone in a rat model of nonalcoholic fatty liver disease. World J Gastroenterol 2008; 14:7240-6. [PMID: 19084941 PMCID: PMC2776884 DOI: 10.3748/wjg.14.7240] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of rosiglitazone (RGZ) on expression of interleukin-18 (IL-18) and caspase-1 in liver of non-alcoholic fatty liver disease (NAFLD) rats.
METHODS: Twenty-eight Sprague-Dawley (SD) rats were randomly divided into control, NAFLD, and RGZ treated NAFLD groups. A NAFLD rat model of NAFLD was established by feeding the animals with a high-fat diet for 12 wk. The NAFLD animals were treated with RGZ or vehicle for the last 4 wk (week 9-12) and then sacrificed to obtain liver tissues. Histological changes were analyzed with HE, oil red O and Masson’s trichrome staining. Expressions of IL-18 and caspase-1 were detected using immunohistochemical staining and semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis.
RESULTS: The expression levels of both IL-18 and caspase-1 were higher in the liver of NAFLD group than in the control group. Steatosis, inflammation and fibrosis, found in the liver of NAFLD rats, were significantly improved 4 wk after RGZ treatment. The elevated hepatic IL-18 and caspase-1 expressions in NAFLD group were also significantly attenuated after RGZ treatment.
CONCLUSION: RGZ treatment can ameliorate increased hepatic IL-18 production and histological changes in liver of NAFLD rats. The beneficial effects of RGZ on NAFLD may be partly due to its inhibitory effect on hepatic IL-18 production.
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Lê KA, Bortolotti M. Role of dietary carbohydrates and macronutrients in the pathogenesis of nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2008; 11:477-82. [PMID: 18542010 DOI: 10.1097/mco.0b013e328302f3ec] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW The prevalence of nonalcoholic fatty liver disease is increasing worldwide and there is strong evidence that dietary factors play a role in its pathogenesis. The present review aims to provide a better understanding of how carbohydrates and other macronutrients may affect the disease. RECENT FINDINGS The effects of carbohydrates on the development of nonalcoholic fatty liver disease differ depending upon the carbohydrate type; high-glycemic index foods are related to increased hepatic fat in both rodents and humans. Similarly, simple carbohydrates, such as fructose, stimulate hepatic de-novo lipogenesis and decrease lipid oxidation, thus leading to increased fat deposition. The underlying mechanisms may involve the activation of transcription factors. Fat intake broadly leads to hepatic fat deposition in rodents but few data are available on humans. Both carbohydrates and fat trigger inflammatory factors, which are closely related to metabolic disorders and nonalcoholic fatty liver disease. Lifestyle interventions appear to be the most appropriate first-line treatment for nonalcoholic fatty liver disease. SUMMARY There is strong evidence that the diet may affect the development of nonalcoholic fatty liver disease. Although simple carbohydrates are clearly shown to have deleterious effects in humans, the role of fat remains controversial. Further studies will be required to evaluate the effects of macronutrient composition on the development of nonalcoholic fatty liver disease.
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Affiliation(s)
- Kim-Anne Lê
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
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Wang BF, Zhu SJ, Tian PY. Establishment of a cellular model of non-alcoholic fatty liver and its biological characteristics. Shijie Huaren Xiaohua Zazhi 2007; 15:3674-3677. [DOI: 10.11569/wcjd.v15.i35.3674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish non-alcoholic fatty liver and non-alcoholic steatohepatitis models at a cellular level.
METHODS: Liver cells HL-7702 were cultured with RPMI-1640 medium containing long chain fat emulsion, which is a nutritional emulsion used in the clinic. Cells were subcultured for two generations to obtain non-alcoholic steatohepatitis models. The similarities between the cellular and animal models were evaluated, especially the utility of the cellular model.
RESULTS: After 48 hours in culture, the TG content in HL-7702 cells cultured in RPMI-1640 medium containing long chain fat emulsion increased remarkably, while there were few variations in biochemical indices such as ALT. When these cells were subcultured for two generations, they showed inflammatory injury.
CONCLUSION: Cellular models of non-alcoholic fatty liver and non-alcoholic steatohepatitis in vivo can be generated in a short time by mixing medium with long chain fat emulsion.
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