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Reza-Zaldívar E, Jacobo-Velázquez DA. Targeting Metabolic Syndrome Pathways: Carrot microRNAs As Potential Modulators. ACS OMEGA 2024; 9:21891-21903. [PMID: 38799337 PMCID: PMC11112692 DOI: 10.1021/acsomega.3c09633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/11/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024]
Abstract
Metabolic syndrome is a condition characterized by metabolic alterations that culminate in chronic noncommunicable diseases of high morbidity and mortality, such as cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease, and colon cancer. Developing new therapeutic strategies with a multifactorial approach is important since current therapies focus on only one or two components of the metabolic syndrome. In this sense, plant-based gene regulation represents an innovative strategy to prevent or modulate human metabolic pathologies, including metabolic syndrome. Here, using a computational and systems biology approach, it was found that carrot microRNAs can modulate key BMPs/SMAD signaling members, C/EBPs, and KLFs involved in several aspects associated with metabolic syndrome, including the hsa04350:TGF-beta signaling pathway, hsa04931:insulin resistance, hsa04152:AMPK signaling pathway, hsa04933:AGE-RAGE signaling pathway in diabetic complications, hsa04010:MAPK signaling pathway, hsa04350:TGF-beta signaling pathway, hsa01522:endocrine resistance, and hsa04910:insulin signaling pathway. These data demonstrated the potential applications of carrot microRNAs as effective food-based therapeutics for obesity and associated metabolic diseases.
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Affiliation(s)
- Edwin
E. Reza-Zaldívar
- Tecnologico
de Monterrey, Institute for Obesity Research, Ave. General Ramon Corona 2514, Zapopan 45201, Jalisco, Mexico
| | - Daniel A. Jacobo-Velázquez
- Tecnologico
de Monterrey, Institute for Obesity Research, Ave. General Ramon Corona 2514, Zapopan 45201, Jalisco, Mexico
- Tecnologico
de Monterrey, Escuela de Ingeniería y Ciencias, Ave. General Ramon Corona 2514, Zapopan 45138, Jalisco, Mexico
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Zhao T, Lun S, Yan M, Park J, Wang S, Chen C. 6,7-Dimethoxycoumarin, Gardenoside and Rhein combination improves non-alcoholic fatty liver disease in rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117646. [PMID: 38135236 DOI: 10.1016/j.jep.2023.117646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 12/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE This study explores the potential therapeutic benefits of using a three-component DGR (composed of specific compounds) to target the NLRP3 inflammasome in the context of non-alcoholic fatty liver disease (NAFLD). AIM OF THE STUDY To assess the impact of a three-component DGR on NAFLD, specifically examining its effects on liver lipid accumulation, inflammation, and the diversity of intestinal microbial communities. METHODS NAFLD was induced in 8-week-old Sprague Dawley rats by feeding them a high-fat emulsion diet every morning for 8 consecutive weeks. Oral administration of DGR or its constituent equivalents in the afternoon. The pharmacological effects of DGR were evaluated using H&E, ORO and ELISA methods to determine the changes in serum and liver tissue indexes of rat-models. Immunohistochemical staining and Western blot were used to assess the interaction between DGR, NLRP3 and IL-1β. RESULTS The induction of NAFLD resulted in elevated hepatic triglycerides (TG), total cholesterol (TC), and free fatty acids (FFA). However, these alterations were ameliorated upon administration of DGR. It is noteworthy that DGR exhibited superior efficacy in comparison to its constituent compounds, manifesting augmented antioxidant activity, diminished hepatic damage, and the attenuation of pro-inflammatory factors. Both DGR and its individual monomeric constituents exhibited the capacity to attenuate the activation of the NLRP3 inflammasome in the liver, leading to an amelioration of the pathological characteristics associated with NAFLD. An analysis of the intestinal flora unveiled an elevated abundance of p_Firmicutes (1.1-fold), p_Cyanobacteria (5.76-fold), and p_Verrucomicrobia (5.2-fold), accompanied by a heightened p_Firmicutes to p_Bacteroidetes ratio (5.49-fold). CONCLUSIONS In the non-alcoholic fatty liver disease (NAFLD) rat model, the concurrent administration of three-component DGR effectively regulated lipid deposition, suppressed liver inflammation, and restored balance in the intestinal flora, thereby improving NAFLD pathology. These findings propose a promising therapeutic strategy for NAFLD, centered on inhibiting the NLRP3 inflammasome through the use of the three-component DGR.
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Affiliation(s)
- Tianyi Zhao
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Shiyi Lun
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Maoying Yan
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - JongPil Park
- Department of Pharmaceutical Engineering, Daegu Haany University, Gyeongsan, 38610, Republic of Korea
| | - Shumin Wang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, PR China.
| | - Changbao Chen
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, PR China.
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Liao K, Yang Q, Xu Y, He Y, Wang J, Li Z, Wu C, Hu J, Wang X. Identification of signature of tumor-infiltrating CD8 T lymphocytes in prognosis and immunotherapy of colon cancer by machine learning. Clin Immunol 2023; 257:109811. [PMID: 37858752 DOI: 10.1016/j.clim.2023.109811] [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: 07/30/2022] [Revised: 09/25/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND To explore the specific marker of CD8+ T cell subsets which are closely related to the prognosis and immunotherapy of patients with colon cancer. METHODS 18 kinds of immune cell expression profile data sets were obtained from GEO database. Compared with other immune cell types, the specific markers of CD8 (+) T cells (TI-CD8) in colorectal cancer were screened. Regression analyses were used to further screen prognostic related genes and construct a prognostic evaluation model. The patients were stratified and analyzed according to the risk scores, KRAS mutation status, stage, lymphatic infiltration and other indicators. The landscape of infiltration level, mutation and copy number variation of immune subsets in high and low TI-CD8Sig score groups were compared and analyzed. The difference of drug response between high and low TI-CD8Sig score groups was analyzed. Differential expression of the model genes was verified by the HPA database. RESULTS Six prognostic-related CD8T cell-specific gene targets were further screened, and the prognostic evaluation model was constructed. The AUC value of the model is >0.75. FAT3 and UNC13C showed a high mutation state in the low-risk group, while USH2A, MUC5B et al. specifically showed a high mutation state in the high-risk group. Compared with the low-risk group, the high-risk group had lower effective rate of drug response. The expression of PD-1 gene was positively correlated with the level of TI-CD8Sig score. CONCLUSION The risk assessment model based on CD8T cell-specific marker genes can effectively predict the prognosis and the drug response of patients with CRC.
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Affiliation(s)
- Kaili Liao
- Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Jiangxi Province Key Laboratory of Laboratory Medicine, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Qijun Yang
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Yuhan Xu
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Yingcheng He
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Jingyi Wang
- School of Public Health of Nanchang University, Nanchang, Jiangxi 330001, China
| | - Zimeng Li
- School of Public Health of Nanchang University, Nanchang, Jiangxi 330001, China
| | - Chengfeng Wu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Jialing Hu
- Department of Emergency, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Xiaozhong Wang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Jiangxi Province Key Laboratory of Laboratory Medicine, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, No. 1 Minde Road, Nanchang, Jiangxi 330006, China.
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Kweon SM, Irimia-Dominguez J, Kim G, Fueger PT, Asahina K, Lai KK, Allende DS, Lai QR, Lou CH, Tsark WM, Yang JD, Ng DS, Lee JS, Tso P, Huang W, Lai KKY. Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose. Am J Physiol Gastrointest Liver Physiol 2023; 325:G147-G157. [PMID: 37129245 PMCID: PMC10393367 DOI: 10.1152/ajpgi.00011.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/03/2023]
Abstract
Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.
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Affiliation(s)
- Soo-Mi Kweon
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Jose Irimia-Dominguez
- Department of Molecular and Cellular Endocrinology and Comprehensive Metabolic Phenotyping Core, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Gayeoun Kim
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Patrick T Fueger
- Department of Molecular and Cellular Endocrinology and Comprehensive Metabolic Phenotyping Core, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States
- City of Hope Comprehensive Cancer Center, Duarte, California, United States
| | - Kinji Asahina
- Central Research Laboratory, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan
| | - Keith K Lai
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, United States
- Contra Costa Pathology Associates, Pleasant Hill, California, United States
| | - Daniela S Allende
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, United States
| | - Quincy R Lai
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Chih-Hong Lou
- Gene Editing and Viral Vector Core, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Walter M Tsark
- Transgenic/Knockout Mouse Program, Center for Comparative Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Dominic S Ng
- Departments of Medicine, Physiology, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States
- City of Hope Comprehensive Cancer Center, Duarte, California, United States
| | - Keane K Y Lai
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States
- City of Hope Comprehensive Cancer Center, Duarte, California, United States
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Fu Q, Cheung WA, Majnik AV, Ke X, Pastinen T, Lane RH. Adverse Maternal Environments Perturb Hepatic DNA Methylome and Transcriptome Prior to the Adult-Onset Non-Alcoholic Fatty Liver Disease in Mouse Offspring. Nutrients 2023; 15:2167. [PMID: 37432267 DOI: 10.3390/nu15092167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 07/12/2023] Open
Abstract
Exposure to adverse early-life environments (AME) increases the incidence of developing adult-onset non-alcoholic fatty liver disease (NAFLD). DNA methylation has been postulated to link AME and late-onset diseases. This study aimed to investigate whether and to what extent the hepatic DNA methylome was perturbed prior to the development of NAFLD in offspring exposed to AME in mice. AME constituted maternal Western diet and late-gestational stress. Male offspring livers at birth (d0) and weaning (d21) were used for evaluating the DNA methylome and transcriptome using the reduced representation of bisulfite sequencing and RNA-seq, respectively. We found AME caused 5879 differentially methylated regions (DMRs) and zero differentially expressed genes (DEGs) at d0 and 2970 and 123, respectively, at d21. The majority of the DMRs were distal to gene transcription start sites and did not correlate with DEGs. The DEGs at d21 were significantly enriched in GO biological processes characteristic of liver metabolic functions. In conclusion, AME drove changes in the hepatic DNA methylome, which preceded perturbations in the hepatic metabolic transcriptome, which preceded the onset of NAFLD. We speculate that subtle impacts on dynamic enhancers lead to long-range regulatory changes that manifest over time as gene network alternations and increase the incidence of NAFLD later in life.
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Affiliation(s)
- Qi Fu
- Department of Research Administration, Children's Mercy Hospital, Kansas City, MO 64108, USA
| | - Warren A Cheung
- Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO 64108, USA
| | - Amber V Majnik
- Department of Pediatrics, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Xingrao Ke
- Department of Research Administration, Children's Mercy Hospital, Kansas City, MO 64108, USA
| | - Tomi Pastinen
- Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO 64108, USA
| | - Robert H Lane
- Department of Administration, Children's Mercy Hospital, Kansas City, MO 64108, USA
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Qin Z, Wang P, Chen W, Wang JR, Ma X, Zhang H, Zhang WJ, Wei C. Hepatic ELOVL3 is dispensable for lipid metabolism in mice. Biochem Biophys Res Commun 2023; 658:128-135. [PMID: 37030067 DOI: 10.1016/j.bbrc.2023.03.075] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/24/2023] [Accepted: 03/29/2023] [Indexed: 04/04/2023]
Abstract
Very long-chain fatty acid elongase 3 (ELOVL3) catalyzes the synthesis of C20-C24 fatty acids and is highly expressed in the liver and adipose tissues. The deficiency of Elovl3 exhibits an anti-obesity effect in mice, but the specific role of hepatic ELOVL3 in lipid metabolism remains unclear. Here we demonstrate that hepatic Elovl3 is not required for lipid homeostasis or the pathogenesis of diet-induced obesity and hepatic steatosis. We generated Elovl3 liver-specific knockout mice via Cre/LoxP approach, which maintained normal expression of ELOVL1 or ELOVL7 in the liver. Unexpectedly, the mutant mice did not show significant abnormalities in body weight, liver mass and morphology, liver triglyceride content, or glucose tolerance when fed normal chow or even a low-fat diet. Moreover, deletion of hepatic Elovl3 did not significantly affect body weight gain or hepatic steatosis induced by high-fat diet. Lipidomic analysis revealed that the lipid profiles were not significantly altered by the loss of hepatic Elovl3. Unlike its global knockouts, the mice lacking Elovl3 specifically in liver displayed normal expression of genes involved in hepatic de novo lipogenesis, lipid uptake, or beta-oxidation at the mRNA and protein levels. Collectively, our data indicate that hepatic ELOVL3 is dispensable for metabolic homeostasis or diet-induced metabolic disease.
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7
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Day K, Seale LA, Graham RM, Cardoso BR. Selenotranscriptome Network in Non-alcoholic Fatty Liver Disease. Front Nutr 2021; 8:744825. [PMID: 34869521 PMCID: PMC8635790 DOI: 10.3389/fnut.2021.744825] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Observational studies indicate that selenium may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Transcriptomic exploration of the aetiology and progression of NAFLD may offer insight into the role selenium plays in this disease. This study compared gene expression levels of known selenoprotein pathways between individuals with a healthy liver to those with NAFLD. Publicly available gene expression databases were searched for studies that measured global gene expression in liver samples from patients with steatosis and non-alcoholic steatohepatitis (NASH) and healthy controls (with [HOC] or without [HC] obesity). A subset of five selenoprotein-related pathways (164 genes) were assessed in the four datasets included in this analysis. The gene TXNRD3 was less expressed in both disease groups when compared with HOC. SCLY and SELENOO were less expressed in NASH when compared with HC. SELENOM, DIO1, GPX2, and GPX3 were highly expressed in NASH when compared to HOC. Disease groups had lower expression of iron-associated transporters and higher expression of ferritin-encoding sub-units, consistent with dysregulation of iron metabolism often observed in NAFLD. Our bioinformatics analysis suggests that the NAFLD liver may have lower selenium levels than a disease-free liver, which may be associated with a disrupted iron metabolism. Our findings indicate that gene expression variation may be associated with the progressive risk of NAFLD.
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Affiliation(s)
- Kaitlin Day
- Department of Nutrition, Dietetics, and Food, Monash University, Notting Hill, VIC, Australia
| | - Lucia A Seale
- Pacific Biosciences Research Center, School of Ocean and Earth Science and Technology, University of Hawaii, Honolulu, HI, United States
| | - Ross M Graham
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Barbara R Cardoso
- Department of Nutrition, Dietetics, and Food, Monash University, Notting Hill, VIC, Australia
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Tanwar S, Rhodes F, Srivastava A, Trembling PM, Rosenberg WM. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol 2020; 26:109-133. [PMID: 31969775 PMCID: PMC6962431 DOI: 10.3748/wjg.v26.i2.109] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/18/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a “wound healing” process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
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Affiliation(s)
- Sudeep Tanwar
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
- Department of Gastroenterology, Whipps Cross University Hospital, Barts Health NHS Trust, Leytonstone, London E11 1NR, United Kingdom
| | - Freya Rhodes
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - Ankur Srivastava
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - Paul M Trembling
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - William M Rosenberg
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
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Li T, Yan H, Geng Y, Shi H, Li H, Wang S, Wang Y, Xu J, Zhao G, Lu X. Target genes associated with lipid and glucose metabolism in non-alcoholic fatty liver disease. Lipids Health Dis 2019; 18:211. [PMID: 31805951 PMCID: PMC6894500 DOI: 10.1186/s12944-019-1154-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 11/26/2019] [Indexed: 12/21/2022] Open
Abstract
Background Insulin resistance (IR) and lipid peroxidation are accepted as ‘two-hit’ hypothesis of Non-alcoholic fatty liver disease (NAFLD). However, there are few published research on identifying genes which connect lipid and glucose metabolism by gene microarray. Objective To identify target genes related to lipid and glucose metabolism that might be responsible for the pathogenesis of NAFLD. Methods A rat model of NAFLD was established by feeding male rats with high-fat diet and gene expression profiles of liver tissues were determined using Agilent DNA microarray. We then investigated differentially expressed genes (DEGs) and intersection of them by using Gene Ontology (GO) and Pathway Analyses. Target genes were verified by Real-time polymerase chain reaction (RT-PCR). Results Compared with control, 932 genes, including 783 up-regulated and 149 down-regulated, exhibited differences in expression. The up-regulated genes were involved in biosynthesis, cell development, cell differentiation and down-regulated genes contributed to biological metabolic process, adipokine metabolic pathway and insulin signaling pathway. We identified genes involved in insulin signaling pathway, Notch signaling pathway and lipid synthetic process to be closely related to liver fat accumulation and insulin resistance. Among them, IGFBP7, Notch1 and HMGCR were up-regulated (2.85-fold, 3.22-fold, and 2.06-fold, respectively, all P < 0.05) and ACACB was down-regulated (2.08-fold, P < 0.01). These four genes supposed to connect lipid and glucose metabolism after GO and Pathway analyses. Conclusions These findings provide innovative information on the whole genome expression profile due to high-fat diet feeding, and bring new insight into the regulating effects of genes on the lipid and glucose metabolism of NAFLD.
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Affiliation(s)
- Ting Li
- Health Science Center, Xi'an Jiaotong University, NO.76 Yanta West Road, Xi'an, 710061, China
| | - Hua Yan
- Department of Geratology, Shaanxi Provincal People's Hospital, Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, China
| | - Yan Geng
- Department of Paediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Haitao Shi
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 West 5th Road, Xi'an, 710004, China
| | - Hong Li
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 West 5th Road, Xi'an, 710004, China
| | - Shenhao Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 West 5th Road, Xi'an, 710004, China
| | - Yatao Wang
- Health Science Center, Xi'an Jiaotong University, NO.76 Yanta West Road, Xi'an, 710061, China
| | - Jingyuan Xu
- Health Science Center, Xi'an Jiaotong University, NO.76 Yanta West Road, Xi'an, 710061, China
| | - Gang Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 West 5th Road, Xi'an, 710004, China
| | - Xiaolan Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 West 5th Road, Xi'an, 710004, China. .,Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
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10
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Rossi Sebastiano M, Konstantinidou G. Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy. Int J Mol Sci 2019; 20:E3624. [PMID: 31344914 PMCID: PMC6696099 DOI: 10.3390/ijms20153624] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/22/2019] [Accepted: 07/22/2019] [Indexed: 12/14/2022] Open
Abstract
The deregulation of cancer cell metabolic networks is now recognized as one of the hallmarks of cancer. Abnormal lipid synthesis and extracellular lipid uptake are advantageous modifications fueling the needs of uncontrolled cancer cell proliferation. Fatty acids are placed at the crossroads of anabolic and catabolic pathways, as they are implicated in the synthesis of phospholipids and triacylglycerols, or they can undergo β-oxidation. Key players to these decisions are the long-chain acyl-CoA synthetases, which are enzymes that catalyze the activation of long-chain fatty acids of 12-22 carbons. Importantly, the long-chain acyl-CoA synthetases are deregulated in many types of tumors, providing a rationale for anti-tumor therapeutic opportunities. The purpose of this review is to summarize the last up-to-date findings regarding their role in cancer, and to discuss the related emerging tumor targeting opportunities.
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Butovich IA, Wilkerson A, Bhat N, McMahon A, Yuksel S. On the pivotal role of Elovl3/ELOVL3 in meibogenesis and ocular physiology of mice. FASEB J 2019; 33:10034-10048. [PMID: 31208226 DOI: 10.1096/fj.201900725r] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The purpose of this study was to examine the role of Elovl3 gene in meibogenesis and the impact of ELOVL3 protein ablation on the physiology of the mouse ocular surface and Meibomian glands (MGs). Elovl3 knockout, ELOVL3-ablated (E3hom) mice and their wild type littermates (E3wt) were studied side by side. E3hom mice had abnormal ocular phenotypes such as delayed eye opening, weeping eyes, crusty eyelids, eyelid edema, highly vascularized cornea and tarsal plates (TPs), slit eye, and increased tearing that resemble symptoms observed in human subjects with various forms of dry eye, MG dysfunction and blepharitis. Lipid profiling of E3hom TPs was conducted using chromatography and mass spectrometry. The analyses revealed that the lipid composition of E3hom TPs was strikingly different from that of their E3wt littermates. The mutation affected major classes of meibomian lipids - cholesteryl esters, wax esters, and cholesteryl esters of (O)-acylated w-hydroxy fatty acids. The studies illuminated the central role of ELOVL3 in producing C21:0-C29:0 fatty acids, including odd-chain and branched ones. Ablation of ELOVL3 leads to selective changes in the lipid composition of meibum, making E3hom mice instrumental in studying the mechanisms of the biosynthesis of meibum and modeling various pathologies of human ocular surface and adnexa.-Butovich, I. A., Wilkerson, A., Bhat, N., McMahon, A., Yuksel, S. On the pivotal role of Elovl3/ELOVL3 in meibogenesis and ocular physiology of mice.
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Affiliation(s)
- Igor A Butovich
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,The Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Amber Wilkerson
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Nita Bhat
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Anne McMahon
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Seher Yuksel
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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12
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Arab JP, Arrese M, Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:321-350. [PMID: 29414249 DOI: 10.1146/annurev-pathol-020117-043617] [Citation(s) in RCA: 384] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.
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Affiliation(s)
- Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna A-1090, Austria;
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13
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Kynurenic Acid Protects against Thioacetamide-Induced Liver Injury in Rats. Anal Cell Pathol (Amst) 2018; 2018:1270483. [PMID: 30327755 PMCID: PMC6171262 DOI: 10.1155/2018/1270483] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 02/04/2018] [Accepted: 02/27/2018] [Indexed: 01/15/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening disorder of liver function. Kynurenic acid (KYNA), a tryptophan metabolite formed along the kynurenine metabolic pathway, possesses anti-inflammatory and antioxidant properties. Its presence in food and its potential role in the digestive system was recently reported. The aim of this study was to define the effect of KYNA on liver failure. The Wistar rat model of thioacetamide-induced liver injury was used. Morphological and biochemical analyses as well as the measurement of KYNA content in liver and hepatoprotective herbal remedies were conducted. The significant attenuation of morphological disturbances and aspartate and alanine transaminase activities, decrease of myeloperoxidase and tumor necrosis factor-α, and elevation of interleukin-10 levels indicating the protective effect of KYNA in thioacetamide (TAA) - induced liver injury were discovered. In conclusion, the hepatoprotective role of KYNA in an animal model of liver failure was documented and the use of KYNA in the treatment of ALF was suggested.
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14
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Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats. Nutrients 2018; 10:nu10091215. [PMID: 30200543 PMCID: PMC6165399 DOI: 10.3390/nu10091215] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/25/2018] [Accepted: 08/31/2018] [Indexed: 12/12/2022] Open
Abstract
The objective of this work was to identify the effect of tomato juice on the expression of genes and levels of metabolites related to steatosis in rats. Male Sprague Dawley rats (8 weeks-old) were grouped (6 rats/group) in four experimental groups: NA (normal diet and water), NL (normal diet and tomato juice), HA (high-fat diet and water), and HL (high-fat diet and tomato juice). After an intervention period of 5 weeks, rats were sacrificed and biochemical parameters, biomarkers of oxidative stress, liver metabolites, and gene expression were determined. Although the H diet provoked dislipemia related to steatosis, no changes in isoprostanes or liver malondialdehyde (MDA) were observed. Changes in the gene expression of the HA group were produced by the high consumption of fat, whereas the consumption of tomato juice had different effects, depending on the diet. In the NL group, the genes involved in β-oxidation were upregulated, and in groups NL and HL upregulation of CD36 and downregulation of APOB and LPL were observed. In addition, in the HL group the accumulation of lycopene upregulated the genes FXR and HNF4A, which have been suggested as preventive factors in relation to steatosis. Regarding the metabolomics study, intake of tomato juice stimulated the biosynthesis of glutathione and amino acids of the transulfurization pathway, increasing the levels of metabolites related to the antioxidant response.
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15
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Huang B, Bao J, Cao YR, Gao HF, Jin Y. Cytochrome P450 1A1 (CYP1A1) Catalyzes Lipid Peroxidation of Oleic Acid-Induced HepG2 Cells. BIOCHEMISTRY (MOSCOW) 2018; 83:595-602. [PMID: 29738693 DOI: 10.1134/s0006297918050127] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic hepatic disease associated with excessive accumulation of lipids in hepatocytes. As the disease progresses, oxidative stress plays a pivotal role in the development of hepatic lipid peroxidation. Cytochrome P450 1A1 (CYP1A1), a subtype of the cytochrome P450 family, has been shown to be a vital modulator in production of reactive oxygen species. However, the exact role of CYP1A1 in NAFLD is still unclear. The aim of this study was to investigate the effects of CYP1A1 on lipid peroxidation in oleic acid (OA)-treated human hepatoma cells (HepG2). We found that the expression of CYP1A1 is elevated in OA-stimulated HepG2 cells. The results of siRNA transfection analysis indicated that CYP1A1-siRNA inhibited the lipid peroxidation in OA-treated HepG2 cells. Additionally, compared with siRNA-transfected and benzo[a]pyrene (BaP)-OA-induced HepG2 cells, overexpression of CYP1A1 by BaP further accelerated the lipid peroxidation in OA-treated HepG2 cells. These observations reveal a regulatory role of CYP1A1 in liver lipid peroxidation and imply CYP1A1 as a potential therapeutic target.
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Affiliation(s)
- B Huang
- Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - J Bao
- Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Y-R Cao
- Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - H-F Gao
- Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Y Jin
- Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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16
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Willebrords J, Maes M, Pereira IVA, da Silva TC, Govoni VM, Lopes VV, Crespo Yanguas S, Shestopalov VI, Nogueira MS, de Castro IA, Farhood A, Mannaerts I, van Grunsven L, Akakpo J, Lebofsky M, Jaeschke H, Cogliati B, Vinken M. Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease. Biochim Biophys Acta Mol Basis Dis 2017; 1864:819-830. [PMID: 29246445 DOI: 10.1016/j.bbadis.2017.12.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 11/27/2017] [Accepted: 12/11/2017] [Indexed: 12/14/2022]
Abstract
Pannexins are transmembrane proteins that form communication channels connecting the cytosol of an individual cell with its extracellular environment. A number of studies have documented the presence of pannexin1 in liver as well as its involvement in inflammatory responses. In this study, it was investigated whether pannexin1 plays a role in acute liver failure and non-alcoholic steatohepatitis, being prototypical acute and chronic liver pathologies, respectively, both featured by liver damage, oxidative stress and inflammation. To this end, wild-type and pannexin1-/- mice were overdosed with acetaminophen for 1, 6, 24 or 48h or were fed a choline-deficient high-fat diet for 8weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, lipid accumulation, protein adduct formation, oxidative stress and inflammation. In parallel, in order to elucidate molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. The results of this study show that pannexin1-/- diseased mice present less liver damage and oxidative stress, while inflammation was only decreased in pannexin1-/- mice in which non-alcoholic steatohepatitis was induced. A multitude of genes related to inflammation, oxidative stress and xenobiotic metabolism were differentially modulated in both liver disease models in wild-type and in pannexin1-/- mice. Overall, the results of this study suggest that pannexin1 may play a role in the pathogenesis of liver disease.
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Affiliation(s)
- Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil.
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil.
| | - Veronica Mollica Govoni
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil.
| | - Valéria Veras Lopes
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil.
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Valery I Shestopalov
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, 1638 NW 10th Avenue, 33136 Miami, FL, United States.
| | - Marina Sayuri Nogueira
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, 05508-270 São Paulo, Brazil.
| | - Inar Alves de Castro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, 05508-270 São Paulo, Brazil.
| | - Anwar Farhood
- Department of Pathology, St. David's North Austin Medical Center, 601E 15th Street, 78701 Austin, United States.
| | - Inge Mannaerts
- Department of Liver Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Leo van Grunsven
- Department of Liver Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Jephte Akakpo
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 66160 Kansas City, United States.
| | - Margitta Lebofsky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 66160 Kansas City, United States.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 66160 Kansas City, United States.
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil.
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
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17
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Genomics of human fatty liver disease reveal mechanistically linked lipid droplet-associated gene regulations in bland steatosis and nonalcoholic steatohepatitis. Transl Res 2016; 177:41-69. [PMID: 27376874 DOI: 10.1016/j.trsl.2016.06.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/13/2016] [Accepted: 06/08/2016] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common disorder hallmarked by excessive lipid deposits. Based on our recent research on lipid droplet (LD) formation in hepatocytes, we investigated LD-associated gene regulations in NAFLD of different grades, that is, steatosis vs steatohepatitis by comparing liver biopsies from healthy controls (N = 13) and NAFLD patients (N = 102). On average, more than 700 differentially expressed genes (DEGs) were identified of which 146 are mechanistically linked to LD formation. We identified 51 LD-associated DEGs frequently regulated in patient samples (range ≥5 to ≤102) with the liver-receptor homolog-1(NR5A2), that is, a key regulator of cholesterol metabolism being commonly repressed among 100 patients examined. With bland steatosis, notable regulations involved hypoxia-inducible lipid droplet-associated-protein and diacylglycerol-O-acyltransferase-2 renowned for their role in LD-growth. Conversely, nonalcoholic steatohepatitis-associated DEGs coded for epidermal growth factor receptor and TLR4 signaling with decreased expression of the GTPase Rab5 and the lipid phosphohydrolase PPAP2B thus highlighting adaptive responses to inflammation, LDL-mediated endocytosis and lipogenesis, respectively. Studies with steatotic primary human hepatocyte cultures demonstrated induction of LD-associated PLIN2, CIDEC, DNAAF1, whereas repressed expression of CPT1A, ANGPTL4, and PKLR informed on burdened mitochondrial metabolism. Equally, repressed expression of the B-lymphocyte chemoattractant CXCL13 and STAT4 as well as induced FGF21 evidenced amelioration of steatosis-related inflammation. In-vitro/in-vivo patient sample comparisons confirmed C-reactive protein, SOCS3, NR5A2, and SOD2 as commonly regulated. Lastly, STRING network analysis highlighted potential "druggable" targets with PLIN2, CIDEC, and hypoxia-inducible lipid droplet-associated-protein being confirmed by immunofluorescence microscopy. In conclusion, steatosis and steatohepatitis specific gene regulations informed on the pathogenesis of NAFLD to broaden the perspective of targeted therapies.
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18
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Magee N, Zou A, Zhang Y. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5170402. [PMID: 27822476 PMCID: PMC5086374 DOI: 10.1155/2016/5170402] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/22/2016] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.
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Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - An Zou
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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19
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Lu X, Ji C, Tong W, Lian X, Wu Y, Fan X, Gao Y. Integrated analysis of microRNA and mRNA expression profiles highlights the complex and dynamic behavior of toosendanin-induced liver injury in mice. Sci Rep 2016; 6:34225. [PMID: 27703232 PMCID: PMC5050432 DOI: 10.1038/srep34225] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 09/01/2016] [Indexed: 01/04/2023] Open
Abstract
Triterpenoid Toosendanin (TSN) exhibits a plenty of pharmacological effects in human and great values in agriculture. However, the hepatotoxicity caused by TSN or Melia-family plants containing TSN used in traditional Chinese medicine has been reported, and the mechanisms of TSN-induced liver injury (TILI) still remain largely unknown. In this study, the dose- and time-dependent effects of TSN on mice liver were investigated by an integrated microRNA-mRNA approach as well as the general toxicological assessments. As the results, the dose- and time-dependent liver injury and alterations in global microRNA and mRNA expressions were detected. Particularly, 9-days 80 mg/kg TSN exposure caused most serious liver injury in mice, and the hepatic adaptation to TILI was unexpectedly observed after 21-days 80 mg/kg TSN administration. Based on the pathway analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs at three time points, it revealed that TILI may be caused by glutathione depletion, mitochondrial dysfunction and lipid dysmetabolism, ultimately leading to hepatocytes necrosis in liver, while liver regeneration may play an important role in the hepatic adaptation to TILI. Our results demonstrated that the integrated microRNA-mRNA approach could provide new insight into the complex and dynamic behavior of TILI.
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Affiliation(s)
- Xiaoyan Lu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Cai Ji
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei Tong
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xueping Lian
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ying Wu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yue Gao
- Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China
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20
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Comparative analysis of gene expression profiles of OPN signalling pathway in four kinds of liver diseases. J Genet 2016; 95:741-50. [DOI: 10.1007/s12041-016-0673-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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21
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Mashek DG, Khan SA, Sathyanarayan A, Ploeger JM, Franklin MP. Hepatic lipid droplet biology: Getting to the root of fatty liver. Hepatology 2015; 62:964-7. [PMID: 25854913 PMCID: PMC4549163 DOI: 10.1002/hep.27839] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 04/04/2015] [Indexed: 12/22/2022]
Abstract
Hepatic steatosis is defined by the accumulation of lipid droplets (LDs). Once thought to be only inert energy storage depots, LDs are increasingly recognized as organelles that have important functions in hepatocytes beyond lipid storage. The lipid and protein composition of LDs is highly dynamic and influences their intrinsic metabolism and signaling properties, which ultimately links them to the changes in hepatic function. This concise review highlights recent discoveries in LD biology and unique aspects of hepatic LDs and their role in liver disease.
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Affiliation(s)
- Douglas G Mashek
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Salmaan A Khan
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | | | - Jonathan M Ploeger
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Mallory P Franklin
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
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22
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Yan S, Yang XF, Liu HL, Fu N, Ouyang Y, Qing K. Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: An update. World J Gastroenterol 2015; 21:3492-3498. [PMID: 25834313 PMCID: PMC4375570 DOI: 10.3748/wjg.v21.i12.3492] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 11/18/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
Long-chain acyl-CoA synthetase (ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer membrance catalyze fatty acids with chain lengths from 12 to 20 carbon atoms to form acyl-CoAs, which are lipid metabolic intermediates and involved in fatty acid metabolism, membrane modifications and various physiological processes. Gain- or loss-of-function studies have shown that the expression of individual ACSL isoforms can alter the distribution and amount of intracellular fatty acids. Changes in the types and amounts of fatty acids, in turn, can alter the expression of intracellular ACSLs. ACSL family members affect not only the proliferation of normal cells, but the proliferation of malignant tumor cells. They also regulate cell apoptosis through different signaling pathways and molecular mechanisms. ACSL members have individual functions in fatty acid metabolism in different types of cells depending on substrate preferences, subcellular location and tissue specificity, thus contributing to liver diseases and metabolic diseases, such as fatty liver disease, obesity, atherosclerosis and diabetes. They are also linked to neurological disorders and other diseases. However, the mechanisms are unclear. This review addresses new findings in the classification and properties of ACSLs and the fatty acid metabolism-associated effects of ACSLs in diseases.
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23
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Lan X, Li D, Zhong B, Ren J, Wang X, Sun Q, Li Y, Liu L, Liu L, Lu S. Identification of differentially expressed genes related to metabolic syndrome induced with high-fat diet in E3 rats. Exp Biol Med (Maywood) 2015; 240:235-241. [PMID: 25294893 PMCID: PMC4935314 DOI: 10.1177/1535370214554531] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 08/15/2014] [Indexed: 12/20/2022] Open
Abstract
Understanding the genes differentially expressing in aberrant organs of metabolic syndrome (MetS) facilitates the uncovering of molecular mechanisms and the identification of novel therapeutic targets for the disease. This study aimed to identify differentially expressed genes related to MetS in livers of E3 rats with high-fat-diet-induced metabolic syndrome (HFD-MetS). E3 rats were fed with high-fat diet for 24 weeks to induce MetS. Then, suppression subtractive hybridization (SSH) technology was used to identify the genes differentially expressed between HFD-MetS and control E3 rat livers. Twenty positive recombinant clones were chosen randomly from forward subtractive library and sent to sequence. BLAST analysis in GenBank database was used to determine the property of each cDNA fragment. In total, 11 annotated genes, 3 ESTs, and 2 novel gene fragments were identified by SSH technology. The expression of four genes (Alb, Pip4k2a, Scd1, and Tf) known to be associated with MetS and other five genes (Eif1, Rnase4, Rps12, Rup2, and Tmsb4) unknown to be relevant to MetS was significantly up-regulated in the livers of HFD-MetS E3 rats compared with control rats using real-time quantitative PCR (RT-qPCR). By analyzing the correlations between the expression of these nine genes and serum concentrations of TG, Tch, HDL-C, and LDL-C, we found that there were significant positive correlations between TG and the expression of five genes (Alb, Eif1, Pip4k2a, Rps12, and Tmsb4x), Tch and three genes (Rnase4, Scd1, and Tmsb4x), and LDL-C and two genes (Rnase4 and Scd1), as well there were significant negative correlations between HDL-C and the expression of three genes (Rup2, Scd1, and Tf). This study provides important clues for unraveling the molecular mechanisms of MetS.
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Affiliation(s)
- Xi Lan
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Dongmin Li
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Bo Zhong
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Juan Ren
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Xuan Wang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Qingzhu Sun
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Yue Li
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Lee Liu
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Li Liu
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
| | - Shemin Lu
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, PR China
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Mikula M, Majewska A, Ledwon JK, Dzwonek A, Ostrowski J. Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver. Int J Mol Med 2014; 34:1647-54. [PMID: 25319795 DOI: 10.3892/ijmm.2014.1958] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Accepted: 09/15/2014] [Indexed: 11/06/2022] Open
Abstract
Obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD), which is characterized by the upregulated expression of two key inflammatory mediators: tumor necrosis factor (Tnfa) and monocyte chemotactic protein 1 (Mcp1; also known as Ccl2). However, the chromatin make-up at these genes in the liver in obese individuals has not been explored. In this study, to identify obesity-mediated epigenetic changes at Tnfa and Ccl2, we used a murine model of obesity induced by a high-fat diet (HFD) and hyperphagic (ob/ob) mice. Chromatin immunoprecipitation (ChIP) assay was used to determine the abundance of permissive histone marks, namely histone H3 lysine 9 and 18 acetylation (H3K9/K18Ac), H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 36 trimethylation (H3K36me3), in conjunction with polymerase 2 RNA (Pol2) and nuclear factor (Nf)-κB recruitment in the liver. Additionally, to correlate the liver tissue-derived ChIP measurements with a robust in vitro transcriptional response at the Tnfa and Ccl2 genes, we used lipopolysaccharide (LPS) treatment to induce an inflammatory response in Hepa1-6 cells, a cell line derived from murine hepatocytes. ChIP revealed increased H3K9/K18Ac at Tnfa and Ccl2 in the obese mice, although the differences were only statistically significant for Tnfa (p<0.05). Unexpectedly, the levels of H3K4me3 and H3K36me3 marks, as well as Pol2 and Nf-κB recruitment, did not correspond with the increased expression of these two genes in the obese mice. By contrast, the acute treatment of Hepa1-6 cells with LPS significantly increased the H3K9/K18Ac marks, as well as Pol2 and Nf-κB recruitment at both genes, while the levels of H3K4me3 and H3K36me3 marks remained unaltered. These results demonstrate that increased Tnfa and Ccl2 expression in fatty liver at the chromatin level corresponds to changes in the level of histone H3 acetylation.
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Affiliation(s)
- Michal Mikula
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland
| | - Aneta Majewska
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw 02-781, Poland
| | - Joanna Karolina Ledwon
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw 02-781, Poland
| | - Artur Dzwonek
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland
| | - Jerzy Ostrowski
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland
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25
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Hennig EE, Mikula M, Goryca K, Paziewska A, Ledwon J, Nesteruk M, Woszczynski M, Walewska-Zielecka B, Pysniak K, Ostrowski J. Extracellular matrix and cytochrome P450 gene expression can distinguish steatohepatitis from steatosis in mice. J Cell Mol Med 2014; 18:1762-72. [PMID: 24913135 PMCID: PMC4196652 DOI: 10.1111/jcmm.12328] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 04/15/2014] [Indexed: 12/22/2022] Open
Abstract
One of the main questions regarding nonalcoholic fatty liver disease is the molecular background of the transition from simple steatosis (SS) to the inflammatory and fibrogenic condition of steatohepatitis (NASH). We examined the gene expression changes during progression from histologically normal liver to SS and NASH in models of obesity caused by hyperphagia or a high-fat diet. Microarray-based analysis revealed that the expression of 1445 and 264 probe sets was changed exclusively in SS and NASH samples, respectively, and 1577 probe sets were commonly altered in SS and NASH samples. Functional annotations indicated that transcriptome alterations that were common for NASH and SS, as well as exclusive for NASH, involved extracellular matrix (ECM)-related processes, although they differed in the type of matrix structure change. The expression of 80 genes was significantly changed in all three comparisons: SS versus control, NASH versus control and NASH versus SS. Of these genes, epithelial membrane protein 1, IKBKB interacting protein and decorin were progressively up-regulated in both SS and NASH compared to normal tissue. The molecular context of interactions of encoded 80 proteins revealed that they are highly interconnected and significantly enriched for processes involving metabolism by cytochrome P450. Validation of 10 selected mRNAs encoding genes related to ECM and cytochrome P450 with quantitative RT-PCR analysis showed consistent changes in their expression during NASH development. The expression profile of these genes has the potential to distinguish NASH from SS and normal tissue and may possibly be beneficial in the clinical diagnosis of NASH.
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Affiliation(s)
- Ewa E Hennig
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland; Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
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26
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Wang G, Li B, Hao Y, Zhi J, He C, Xu C. Correlation analysis between gene expression profile of high-fat emulsion-induced non-alcoholic fatty liver and liver regeneration in rat. Cell Biol Int 2013; 37:917-28. [PMID: 23619824 DOI: 10.1002/cbin.10118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 03/29/2013] [Indexed: 12/21/2022]
Abstract
To explore the relevance of non-alcoholic fatty liver disease (NAFLD) to liver regeneration (LR), rat models of non-alcoholic steatohepatitis (NASH) and LR were established, respectively, then Rat Genome 230 2.0 Array was used to detect the gene expression abundance of them, and the reliabilities of the array data were confirmed by real-time RT-PCR. As a result, the expression of 93 genes was significantly changed during NAFLD occurrence and 948 genes in LR. Hierarchical clustering indicated that the expression profiles of the above two events were quite different. K-means cluster classified their expression patterns into four clusters, and gene expression trends of clusters 1, 2 were similar in NAFLD and LR, while clusters 3, 4 were contrary with the gene expression changes of LR more abundant. DAVID classifications and functional enrichment analysis found that lipid metabolism and carbohydrate metabolism were stronger in NAFLD than in LR, but some other physiological activities including inflammation/immune response, cell adhesion, and migration, cell proliferation and differentiation in NAFLD were weaker than in LR. IPA further indicated that lipid metabolism, inflammation response, and cellular development were highly associated with NAFLD, and thus identified some potential biomarkers for NAFLD.
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Affiliation(s)
- Gaiping Wang
- College of Life Sciences, Henan Normal University, Xinxiang, 453007, Henan Province, China
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27
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Effects of EPA and DHA on lipid droplet accumulation and mRNA abundance of PAT proteins in caprine monocytes. Res Vet Sci 2013; 94:246-51. [DOI: 10.1016/j.rvsc.2012.09.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 09/22/2012] [Accepted: 09/26/2012] [Indexed: 11/19/2022]
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28
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Wang G, Xu C, Zhi J, Hao Y, Zhang L, Chang C. Gene expression profiles reveal significant differences between rat liver cancer and liver regeneration. Gene 2012; 504:41-52. [DOI: 10.1016/j.gene.2012.04.086] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 04/02/2012] [Accepted: 04/27/2012] [Indexed: 02/08/2023]
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29
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Ten paths of PKA signaling pathway regulate hepatocyte proliferation in rat liver regeneration. Genes Genomics 2012. [DOI: 10.1007/s13258-011-0195-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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30
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Wang L, Meng X, Zhang F. Raspberry ketone protects rats fed high-fat diets against nonalcoholic steatohepatitis. J Med Food 2012; 15:495-503. [PMID: 22551412 PMCID: PMC3338106 DOI: 10.1089/jmf.2011.1717] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 12/13/2011] [Indexed: 12/22/2022] Open
Abstract
The protective effect of raspberry ketone against nonalcoholic steatohepatitis (NASH) was tested by using a high-fat diet-induced NASH model, and its mechanism was explored. Forty Sprague-Dawley rats with a 1:1 male to female ratio were randomly divided into five groups: the normal control (NC) group (n=8) fed normal diet for 8 weeks, the model control (MC) group (n=8) fed high-fat diet (82% standard diet, 8.3% yolk powder, 9.0% lard, 0.5% cholesterol, and 0.2% sodium taurocholate), and the raspberry ketone low-dose (0.5%) (RKL) group (n=8), the raspberry ketone middle-dose (1%) (RKM) group (n=8), and the raspberry ketone high-dose (2%) (RKH) group (n=8) fed high-fat diet for 4 weeks. After 8 weeks of experiment, all the rats were sacrificed, and blood lipid parameters (total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), liver function parameters (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]), leptin (LEP), free fatty acid (FFA), tumor necrosis factor α (TNF-α), blood glucose (GLU), and insulin (INS) with calculated INS resistance index (IRI) and INS-sensitive index (ISI) were measured in rats. Therefore, we determined the peroxisome proliferator-activated receptor (PPAR)-α activity in liver homogenate and the levels of low-density lipoprotein receptor (LDLR), high-sensitivity C-reactive protein (hs-CRP), adiponection (APN), superoxide dismutase, and malondialdehyde (MDA). The liver tissues of rats in each group were imaged by electron microscopy with hematoxylin-eosin as the staining agent. The levels of TG, TC, LDL-C, ALT, AST, ALP, GLU, INS, IRI, FFA, LEP, TNF-α, MDA, and hs-CRP of MC rats were significantly increased (P<.05, P<.01). Therefore, the levels of HDL-C, ISI, PPAR-α, LDLR, and APN were significantly decreased (P<.05, P<.01). Compared with the MC group, each parameter in the RKL, RKM, and RKH groups was significantly improved (P<.05, P<.01). Thus raspberry ketone was an effective intervention for NASH in rats. It was believed that raspberry ketone had a dual effect of liver protection and fat reduction, and the mechanism was probably mediated by alleviation of fatty degeneration of liver cells, decreased liver inflammation, correction of dyslipidemia, reversal of LEP and INS resistance, and improved antioxidant capacity.
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Affiliation(s)
- Lili Wang
- College of Food, Shenyang Agricultural University, Shenyang, Liaoning, China
- Shenyang Product Quality Supervision and Inspection Institute, Shenyang, Liaoning, China
| | - Xianjun Meng
- College of Food, Shenyang Agricultural University, Shenyang, Liaoning, China
| | - Fengqing Zhang
- Shenyang Product Quality Supervision and Inspection Institute, Shenyang, Liaoning, China
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