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Fernández-Ramos D, Lopitz-Otsoa F, Lu SC, Mato JM. S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy. Cancers (Basel) 2025; 17:535. [PMID: 39941901 PMCID: PMC11816870 DOI: 10.3390/cancers17030535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.
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Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - José M. Mato
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
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Goand UK, Patel I, Verma S, Yadav S, Maity D, Singh N, Vishwakarma S, Rathaur S, Garg R, Gayen JR. Immunometabolic impact of pancreastatin inhibitor PSTi8 in MCD induced mouse model of oxidative stress and steatohepatitis. Cytokine 2023; 171:156354. [PMID: 37672864 DOI: 10.1016/j.cyto.2023.156354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023]
Abstract
AIM Pancreastatin, a dysglycemic hormone that encourages inflammation and steatosis in a variety of metabolic disorder animal models. The purpose of this study is to determine the effect of the pancreastatin inhibitor PSTi8 on immunometabolic changes in the liver of MCD-induced NASH mice. MAIN METHODS Methionine and choline-deficient (MCD) diet was used for the development of NASH. Liver enzymes like SGOT, SGPT, and ALP and lipid profiles were also performed in the serum. Further, immunophenotyping study was performed in the liver through flowcytometer. Subsequently, Hematoxylin and Eosin, Picro Sirius Red and Masson's Trichrome staining were done to check the liver morphology and collagen staining, respectively. Inflammatory cytokines were measured through ELISA and gene expression through RT-PCR. The expression of α-SMA was examined using immunohistochemistry and immunofluorescence staining. KEY FINDINGS PSTi8 inhibited the expression of lipogenic genes in the liver and attenuated bad cholesterol, SGOT, SGPT, and ALP in the serum. PSTi8 improved the liver morphology and attenuated collagen deposition. Subsequently, PSTi8 attenuated inflammatory M1-macrophages, CD8+T, CD4+T cells and increased anti-inflammatory M2 macrophages, T-reg and eosinophil populations in the liver. It also attenuated the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il6. Apart from this, PSTi8 attenuated the oxidative stress marker, like ROS, and MDA and fibrosis marker α-SMA in the liver. It also decreased the apoptosis and ROS and MDA level in the liver. SIGNIFICANCE Overall, these compressive studies revealed that PSTi8 exhibited beneficial effect on the liver of MCD-induced NASH mice by attenuating inflammation and oxidative stress.
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Affiliation(s)
- Umesh K Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Inklisan Patel
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shubhi Yadav
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Debalina Maity
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Naveen Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sachin Vishwakarma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shivam Rathaur
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Pengnet S, Sumarithum P, Phongnu N, Prommaouan S, Kantip N, Phoungpetchara I, Malakul W. Naringin attenuates fructose-induced NAFLD progression in rats through reducing endogenous triglyceride synthesis and activating the Nrf2/HO-1 pathway. Front Pharmacol 2022; 13:1049818. [PMID: 36588703 PMCID: PMC9797507 DOI: 10.3389/fphar.2022.1049818] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Background: Excessive fructose consumption causes hepatic lipid accumulation via increased triglyceride (TG) synthesis, leading to the development and progression of non-alcoholic fatty liver disease (NALFD). Naringin, a flavanone glycoside found in citrus fruit, has antioxidant and hypolipidemic properties. Therefore, the aim of this study was to investigate the effect of naringin on fructose-induced NAFLD in rats and the possible underlying mechanism. Methods: Male Sprague Dawley rats were given 10% (w/v) fructose in drinking water for 12 weeks. Naringin (100 mg/kg/day) was administered orally to rats for the last 4 weeks of fructose overload. After 12 weeks of treatment, the hepatic lipid content was determined. In addition, the expression of proteins involved in de novo lipogenesis (DNL) and TG synthesis as well as antioxidant and inflammatory mediators in the liver were examined by western blot analysis. Results: Treatment of fructose-fed rats with naringin significantly decreased the hepatic TG and cholesterol content as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. Naringin treatment also decreased the hepatic expression of carbohydrate response element binding protein (ChREBP), sterol regulatory element-binding protein-1c (SREBP-1c) and nuclear SREBP-1c (nSREBP-1c) as well as enzymes involved in DNL (acetyl CoA carboxylase [ACC] and fatty acid synthase [FAS]) and an enzyme involved in TG synthesis (glycerol-3-phosphate acyltransferase 1 [GPAT-1] and diacylglycerol acyltransferase2 [DGAT2]) in fructose-fed rats. In addition, naringin induced a significant decrease in the hepatic expression of nuclear factor kappa B (NF-κB) and tumor necrosis factor α (TNF-α). Furthermore, naringin administration restored the expression of the antioxidant mediators nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in the liver of fructose-fed rats. Conclusion: These results demonstrate that oral administration of naringin protects against fructose-induced hepatic steatosis by decreasing DNL and TG synthesis. In addition, naringin could prevent NAFLD progression via targeting the Nrf2/HO-1 and the NF-κB/TNF-α pathways.
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Affiliation(s)
- Sirinat Pengnet
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Phinsuda Sumarithum
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Nuttaphong Phongnu
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Sakdina Prommaouan
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Napapas Kantip
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Ittipon Phoungpetchara
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Wachirawadee Malakul
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand,*Correspondence: Wachirawadee Malakul,
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Wang L, Dong W, Gao H, Chen C, Liang S, Ye X, Liu Y, Hou Y, Fan L, Pan T, Wang Z, Chen Y, Luo Y, Song L. A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166560. [PMID: 36167161 DOI: 10.1016/j.bbadis.2022.166560] [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: 07/23/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases. METHODS Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 μg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. RESULTS Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT-induced hepatoprotection in primary hepatocytes and in mice with NASH. CONCLUSION rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH.
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Affiliation(s)
- Luyao Wang
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wenliya Dong
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huan Gao
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuchu Chen
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Siyu Liang
- The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xianxi Ye
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Liu
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yushu Hou
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lei Fan
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Clinical Pharmacy Research Center, Jinhua Hospital of Zhejiang University and Jinhua Municipal Central Hospital, Jinhua, Zhejiang 321000, China
| | - Tongtong Pan
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zengshou Wang
- The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yongping Chen
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yongde Luo
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Lintao Song
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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May T, de la Haye B, Nord G, Klatt K, Stephenson K, Adams S, Bollinger L, Hanchard N, Arning E, Bottiglieri T, Maleta K, Manary M, Jahoor F. One-carbon metabolism in children with marasmus and kwashiorkor. EBioMedicine 2022; 75:103791. [PMID: 35030356 PMCID: PMC8761690 DOI: 10.1016/j.ebiom.2021.103791] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 11/24/2021] [Accepted: 12/16/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. METHODS Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. FINDINGS Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L (± SD): 0·549 (± 0·217) P = 0·00045 & 90 (± 40) P < 0·0001, respectively) and kwashiorkor (0·557 (± 0·195) P < 0·0001 & 115 (± 50) P < 0·0001), relative to marasmus (0·698 (± 0·212) & 153 (± 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. INTERPRETATION Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation. FUNDING The Hickey Family Foundation, the American College of Gastroenterology, the NICHD, and the USDA/ARS.
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Affiliation(s)
- Thaddaeus May
- Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston TX, USA.
| | | | | | - Kevin Klatt
- Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston TX, USA,Center for Precision Environmental Health, Baylor College of Medicine
| | | | | | - Lucy Bollinger
- Washington University in St. Louis School of Medicine, USA
| | - Neil Hanchard
- National Institutes of Health, USA,National Human Genome Research Institute, Nationl Institutes of Health
| | - Erland Arning
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute
| | | | - Mark Manary
- Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston TX, USA,The University of Malawi College of Medicine, Malawi,Washington University in St. Louis School of Medicine, USA
| | - Farook Jahoor
- Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston TX, USA
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Shao M, Ye Z, Qin Y, Wu T. Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp Ther Med 2020; 20:26. [PMID: 32934691 PMCID: PMC7471863 DOI: 10.3892/etm.2020.9154] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and can lead to liver cirrhosis or liver cancer in severe cases. In recent years, the incidence of NAFLD has increased substantially. The trend has continued to increase and has become a key point of concern for health systems. NAFLD is often associated with metabolic abnormalities caused by increased visceral obesity, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis and systemic microinflammation. Therefore, the pathophysiological mechanisms of NAFLD must be clarified to develop new drug treatment strategies. Recently, researchers have conducted numerous studies on the pathogenesis of NAFLD and have identified various important regulatory factors and potential molecular mechanisms, providing new targets and a theoretical basis for the treatment of NAFLD. However, the pathogenesis of NAFLD is extremely complex and involves the interrelationship and influence of multiple organs and systems. Therefore, the condition must be explored further. In the present review, the abnormal metabolic process, including glucose, lipid, amino acid, bile acid and iron metabolism are reviewed. It was concluded that NAFLD is associated with an imbalanced metabolic network that involves glucose, lipids, amino acids, bile acids and iron, and lipid metabolism is the core metabolic process. The current study aimed to provide evidence and hypotheses for research and clinical treatment of NAFLD.
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Affiliation(s)
- Mingmei Shao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Zixiang Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Yanhong Qin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Fernández-Ramos D, Lopitz-Otsoa F, Delacruz-Villar L, Bilbao J, Pagano M, Mosca L, Bizkarguenaga M, Serrano-Macia M, Azkargorta M, Iruarrizaga-Lejarreta M, Sot J, Tsvirkun D, van Liempd SM, Goni FM, Alonso C, Martínez-Chantar ML, Elortza F, Hayardeny L, Lu SC, Mato JM. Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation. World J Gastroenterol 2020; 26:5101-5117. [PMID: 32982112 PMCID: PMC7495035 DOI: 10.3748/wjg.v26.i34.5101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/19/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control. AIM To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)] after treatment with Aramchol. METHODS Isolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with 13C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites. RESULTS Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid (FA) synthesis and oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome (P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13C-uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5P/Xyl5P. CONCLUSION Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation.
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Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
- CIBERehd - Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Madrid 28029, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
| | - Laura Delacruz-Villar
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
| | - Jon Bilbao
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
| | - Martina Pagano
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy
| | - Laura Mosca
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy
| | - Maider Bizkarguenaga
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
| | - Marina Serrano-Macia
- Liver Disease Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Spain
| | - Mikel Azkargorta
- Proteomics Platform, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Spain
| | | | - Jesús Sot
- Instituto Biofisika (UPV/EHU, CSIC), Leioa 48940, Spain; Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Leioa 48940, Spain
| | - Darya Tsvirkun
- Pre-clinical and Chemistry, Manufacturing and Controls, Galmed Pharmaceuticals, Tel Aviv 6578317, Israel
| | | | - Felix M Goni
- Instituto Biofisika (UPV/EHU, CSIC), Leioa 48940, Spain; Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Leioa 48940, Spain
| | | | - María Luz Martínez-Chantar
- CIBERehd - Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Madrid 28029, Spain
- Liver Disease Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Spain
| | - Felix Elortza
- Proteomics Platform, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Spain
| | - Liat Hayardeny
- Pre-clinical and Chemistry, Manufacturing and Controls, Galmed Pharmaceuticals, Tel Aviv 6578317, Israel
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - José M Mato
- Precision Medicine and Metabolism Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), Derio 48160, Bizkaia, Spain
- CIBERehd - Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Madrid 28029, Spain
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Si-Wu-Tang Alleviates Nonalcoholic Fatty Liver Disease via Blocking TLR4-JNK and Caspase-8-GSDMD Signaling Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8786424. [PMID: 32849904 PMCID: PMC7439165 DOI: 10.1155/2020/8786424] [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: 04/30/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) has high global prevalence; however, the treatments of NAFLD are limited due to lack of approved drugs. Methods Mice were randomly assigned into three groups: Control group, NAFLD group, NAFLD plus Si-Wu-Tang group. A NAFLD mice model was established by feeding with a methionine- and choline-deficient (MCD) diet for four weeks. Si-Wu-Tang was given orally by gastric gavage at the beginning of 3rd week, and it lasted for two weeks. The treatment effects of Si-Wu-Tang were confirmed by examining the change of body weight, serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels, Oil Red O staining, and hematoxylin and eosin (H&E) staining of the liver samples and accompanied by steatosis grade scores. The expression and activation of the possible signaling proteins involved in the pathogenesis of NAFLD were determined by western blotting. Results Mice fed with four weeks of MCD diet displayed elevated serum levels of ALT and AST, while there was decreased body weight. The hepatic Oil Red O staining and H&E staining showed severe liver steatosis with high steatosis grade scores. All these can be improved by treating with Si-Wu-Tang for two weeks. Mechanistically, the increased hepatic TLR4 expression and its downstream JNK phosphorylation induced by MCD diet were suppressed by Si-Wu-Tang. Moreover, the upregulations of Caspase-8, gasdermin D (GSDMD), and cleaved-GSDMD in liver mediated by MCD diet were all inhibited by Si-Wu-Tang. Conclusions Treatment with Si-Wu-Tang improves MCD diet-induced NAFLD in part via blocking TLR4-JNK and Caspase-8-GSDMD signaling pathways, suggesting that Si-Wu-Tang has potential for clinical application in treating NAFLD.
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Loss of Hepatocyte-Specific PPAR γ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet. PPAR Res 2020; 2020:9735083. [PMID: 32411189 PMCID: PMC7211257 DOI: 10.1155/2020/9735083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/16/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.
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10
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Chandrasekaran P, Murugan S, Richard E, Bethapudi B, Purusothaman D, Velusami C, D'Souza P, Mundkinajeddu D, Talkad M. Evaluation of lipotropic effect of herbal formulation on hepatic fat accumulation in rats fed with methionine-choline deficient diet. Pharmacogn Mag 2019. [DOI: 10.4103/pm.pm_111_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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11
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Du J, Cao X, Diao J, Zhang Q, Peng C, Li J, Xiao X. Neonatal overfeeding in mice aggravates the development of methionine and choline-deficient diet-induced steatohepatitis in adulthood. Genes Dis 2018; 6:68-77. [PMID: 30906835 PMCID: PMC6411625 DOI: 10.1016/j.gendis.2017.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/23/2017] [Indexed: 12/01/2022] Open
Abstract
Overfeeding in early life is associated with obesity and insulin resistance in adulthood. In the present study, a well-characterized mouse model was used to investigate whether neonatal overfeeding increases susceptibility to the development of non-alcoholic steatohepatitis (NASH) following feeding with a methionine and choline- deficient (MCD) diet. Neonatal overfeeding was induced by adjusting litters to 3 pups per dam (small litter size, SL) in contrast to 10 pups per dam as control (normal litter size, NL). At 11 weeks of age, mice were fed with standard (S) or a methionine and choline-deficient (MCD) diet for 4 weeks. Glucose tolerance tests, tissue staining with haematoxylin and eosin, oil-red O and immunohistochemistry for F4/80, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed. Compared with NL mice, SL mice exhibited higher body weight gain from 2 weeks of age throughout adulthood, and more profound glucose intolerance as adults. Sterol regulatory element-binding protein 1c and fatty acid synthase mRNA expression levels in liver were upregulated in SL mice at 3 weeks of age. MCD diet induced typical NASH, especially in SL-MCD mice, evidenced by marked fat accumulation, macrovescular steatosis, ballooned hepatocytes, inflammatory cells infiltration and tumour necrosis factor-α mRNA upregulation in the liver, as well as increased alanine aminotransferase and aspartate aminotransferase levels in the serum. There were no significant differences in liver fibrosis in all groups. Overfeeding during early life exhibited effect with administration of MCD diet in inducing adverse effects on the metabolic function and in promoting the progression of NASH in mice, possibly mediated through dysregulated lipid metabolism in hepatocytes and aggravated hepatic inflammation.
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Affiliation(s)
- Juan Du
- Laboratory of Lipid & Glucose Metabolism, PR China
| | - Xuemei Cao
- Laboratory of Lipid & Glucose Metabolism, PR China
| | - Junlin Diao
- Laboratory of Lipid & Glucose Metabolism, PR China
| | - Qijuan Zhang
- Department of Clinical Nutrition, The First Affiliated Hospital of Chongqing Medical University, PR China
| | - Chuan Peng
- Laboratory of Lipid & Glucose Metabolism, PR China
| | - Jibin Li
- School of Public Health and Management, Chongqing Medical University, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing, 400016, PR China
| | - Xiaoqiu Xiao
- Laboratory of Lipid & Glucose Metabolism, PR China
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Kim MS, Kim SH, Park SJ, Sung MJ, Park J, Hwang JT, Yang HJ, Kim S, Seo D, Shin SS, Hur HJ. Ginseng berry improves hyperglycemia by downregulating hepatic gluconeogenesis and steatosis in mice with diet-induced type 2 diabetes. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.05.050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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13
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Wahlang B, Perkins JT, Petriello MC, Hoffman JB, Stromberg AJ, Hennig B. A compromised liver alters polychlorinated biphenyl-mediated toxicity. Toxicology 2017; 380:11-22. [PMID: 28163111 DOI: 10.1016/j.tox.2017.02.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 01/10/2017] [Accepted: 02/01/2017] [Indexed: 12/17/2022]
Abstract
Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9mg/kg) or the PCB mixture, Arcolor1260 (20mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases.
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Affiliation(s)
- Banrida Wahlang
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536, USA
| | - Jordan T Perkins
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA
| | - Michael C Petriello
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536, USA
| | - Jessie B Hoffman
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA; Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Arnold J Stromberg
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington, KY, 40536, USA
| | - Bernhard Hennig
- Superfund Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY, 40536, USA; Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
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Kirman C, Hughes B, Becker R, Hays S. Derivation of a No-significant-risk-level (NSRL) for dermal exposures to diethanolamine. Regul Toxicol Pharmacol 2016; 76:137-51. [DOI: 10.1016/j.yrtph.2016.01.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 01/28/2016] [Accepted: 01/29/2016] [Indexed: 11/15/2022]
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Giles DA, Moreno-Fernandez ME, Stankiewicz TE, Cappelletti M, Huppert SS, Iwakura Y, Dong C, Shanmukhappa SK, Divanovic S. Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis. PLoS One 2016; 11:e0149783. [PMID: 26895034 PMCID: PMC4760740 DOI: 10.1371/journal.pone.0149783] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 02/04/2016] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.
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Affiliation(s)
- Daniel A. Giles
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Maria E. Moreno-Fernandez
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Traci E. Stankiewicz
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Monica Cappelletti
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Stacey S. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Yoichiro Iwakura
- Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Chen Dong
- Department of Immunology, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Shiva K. Shanmukhappa
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Senad Divanovic
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- * E-mail:
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Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2016; 113:2288-93. [PMID: 26858440 DOI: 10.1073/pnas.1525093113] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.
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Pisonero-Vaquero S, Martínez-Ferreras Á, García-Mediavilla MV, Martínez-Flórez S, Fernández A, Benet M, Olcoz JL, Jover R, González-Gallego J, Sánchez-Campos S. Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver disease. Mol Nutr Food Res 2015; 59:879-93. [PMID: 25712622 DOI: 10.1002/mnfr.201400913] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/03/2015] [Accepted: 02/09/2015] [Indexed: 12/12/2022]
Abstract
SCOPE Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. METHODS AND RESULTS We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. CONCLUSION These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.
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The antitumor effect of formosanin C on HepG2 cell as revealed by 1H-NMR based metabolic profiling. Chem Biol Interact 2014; 220:193-9. [PMID: 25014414 DOI: 10.1016/j.cbi.2014.06.023] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 12/26/2022]
Abstract
Formosanin C (FC) is a pure compound isolated from Rhizoma Paridis. In the past years, antitumor effects of FC have been observed in several cultural cells and animal systems. However, there was no research particular on liver cancer. In this experiment, 3-(4, 5-dimethylthiazol diphenyltetrazolium bromide (MTT) dye reduction assay was used to evaluate cell viability of HepG2 cells with FC-treatment. 4', 6-diamidino-2-phenylindole (DAPI) staining, Annexin V-FITC/PI assay and DNA fragment assay were applied to observe FC-induced apoptosis. Cell cycle analysis and NMR metabolic profiles were used to identify molecular mechanisms of FC in HepG2 cells. As a result, FC inhibited the growth of HepG2 cells through inducing apoptosis and S phase arrest. Cells cultured in the presence or absence of FC was different in metabolic profiles. The treatment decreased acetate, ethanol, choline and betaine, and increased butyrate, fatty acids, leucine and valine in HepG2 cells. In conclusion, metabolomic analysis of the exometabolome of FC-treated HepG2 cells, together with traditional methods such as apoptosis test and cell cycle analysis provided a holistic method for elucidating mechanisms of potential anti-cancer drug, FC.
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Stanković MN, Mladenović DR, Duričić I, Šobajić SS, Timić J, Jorgačević B, Aleksić V, Vučević DB, Ješić-Vukićević R, Radosavljević TS. Time-dependent changes and association between liver free fatty acids, serum lipid profile and histological features in mice model of nonalcoholic fatty liver disease. Arch Med Res 2014; 45:116-124. [PMID: 24480733 DOI: 10.1016/j.arcmed.2013.12.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/24/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Methionine-choline deficient (MCD) diet duration necessary for development of non-alcoholic fatty liver disease (NAFLD) and the dynamic of lipid profile and fatty acids are not completely established. The study examined dynamics and association between liver free fatty acids (FFA), serum lipid profile and liver morphological changes on MCD diet-induced NAFLD in mice. METHODS Male C57BL/6 mice (n = 28) were divided into four groups (n = 7 per group): control: fed with standard chow, MCD diet-fed groups: 2, 4 or 6 weeks. After treatment, liver and blood samples were taken for histopathology, serum lipid profile, and liver FFA composition. RESULTS Hepatic FFA profile showed a decrease in saturated acids, arachidonic and docosahexaenoic acid, whereas proportions of docosapentaenoic, oleic and linoleic acid were increased. Total cholesterol, HDL and triglycerides progressively decreased, whereas LDL level progressively increased. Focal fatty change in the liver appeared after 2 weeks, whereas diffuse fatty change with severe inflammation and ballooned hepatocytes were evident after 6 weeks. CONCLUSIONS Six-week diet model may be appropriate for investigation of the role of lipotoxicity in the progression of NAFLD. Therefore, supplementation with n-3 polyunsaturated acid like DHA, rather than DPA, especially in the initial stage of fatty liver disease, may potentially have preventive effects and alleviate development of NAFLD/NASH and may also potentially reduce cardiovascular risk by moderating dyslipidemia.
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Affiliation(s)
- Milena N Stanković
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia
| | - Dušan R Mladenović
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia
| | - Ivana Duričić
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Slađana S Šobajić
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jasmina Timić
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Bojan Jorgačević
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia
| | - Vuk Aleksić
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia
| | - Danijela B Vučević
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia
| | | | - Tatjana S Radosavljević
- Faculty of Medicine, Institute of Pathophysiology "Ljubodrag Buba Mihailović", University of Belgrade, Belgrade, Serbia.
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Laggai S, Simon Y, Ranssweiler T, Kiemer AK, Kessler SM. Rapid chromatographic method to decipher distinct alterations in lipid classes in NAFLD/NASH. World J Hepatol 2013; 5:558-567. [PMID: 24179615 PMCID: PMC3812458 DOI: 10.4254/wjh.v5.i10.558] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 09/10/2013] [Accepted: 10/12/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a simple method to quantify lipid classes in liver diseases and to decipher the lipid profile in p62/IMP2-2/IGF2BP2-2 transgenic mice.
METHODS: Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein p62/IMP2-2/IGF2BP2-2 was used as a model for steatosis. Steatohepatitis was induced by feeding a methionine-choline deficient diet. Steatosis was assessed histologically. For thin layer chromatographic analysis, lipids were extracted from freeze-dried tissues by hexane/2-propanol, dried, redissolved, and chromatographically separated by a two-solvent system. Dilution series of lipid standards were chromatographed, detected, and quantified. The detection was performed by either 2’,7’-dichlorofluoresceine or a sulfuric acid/ethanol mixture.
RESULTS: Histological analyses confirmed steatosis and steatohepatitis development. The extraction, chromatographic, and detection method showed high inter-assay reproducibility and allowed quantification of the different lipid classes. The analyses confirmed an increase of triglycerides and phosphatidylethanolamine and a decrease in phosphatidylcholine in the methionine-choline deficient diet. The method was used for the first time to asses the lipid classes induced in the p62-overexpressing mouse model and showed a significant increase in all detected lipid species with a prominent increase of triglycerides by 2-fold. Interestingly, the ratio of phosphatidylcholine to phosphatidylethanolamine was decreased, as previously suggested as a marker in the progression from steatosis to steatohepatitis.
CONCLUSION: The thin layer chromatography analysis allows a reliable quantification of lipid classes and provides detailed insight into the lipogenic effect of p62.
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