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Xin X, Zhang Q, Xu J, Huang J. Effect of Dietary Magnesium on the Association Between Serum Uric Acid and Female Infertility. Int J Womens Health 2025; 17:33-42. [PMID: 39802919 PMCID: PMC11725261 DOI: 10.2147/ijwh.s484872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
Background Few studies have evaluated the correlation between serum uric acid (SUA) levels and the prevalence of female infertility in the general population, and the effect of magnesium intake on this correlation has not been investigated. Methods All participants aged 18-45 years at baseline were enrolled from the National Health and Nutritional Examination Surveys (NHANES) 2013-2018. The continuous variable of SUA was divided into quartile (Q1: ≤3.7 mg/dL, Q2: 3.7-4.4 mg/dL, Q3: 4.4-5.1 mg/dL, Q4: ≥5.1 mg/dL). Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Dietary magnesium was divided into two groups based on the median number of participants (low magnesium intake, <243 mg/day; high magnesium intake, ≥243 mg/day). Results A total of 3185 female participants were included in the final analysis, 10.58% of whom were infertile. In the full adjustment model, SUA was positively associated with female infertility (OR=1.13, 95% CI: 1.01-1.27). Compared to the lowest quartile (Q1), female participants with the highest SUA levels (Q4) had an increased risk of infertility by 62% (OR=1.62, 95% CI: 1.1-2.4). Moreover, we found an interactive effect of magnesium intake on the association between SUA and infertility in adjusted models (interaction likelihood ratio test: P=0.029), implying that high magnesium intake may ameliorate the association between SUA and female infertility. Conclusion This study is the first to report an interactive effect of dietary magnesium intake on the relationship between SUA and female infertility.
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Affiliation(s)
- Xiaoqin Xin
- Department of Clinical Laboratory, Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China
| | - Qi Zhang
- Department of Obstetrics and Gynecology, Ganzhou Maternal and Child Health Hospital, Ganzhou, Jiangxi, People’s Republic of China
| | - Jing Xu
- Department of Clinical Laboratory, Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China
| | - Jungao Huang
- Department of Medical Genetic, Ganzhou Maternal and Child Health Hospital, Ganzhou, Jiangxi, 341000, People’s Republic of China
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Spaggiari R, Angelini S, Di Vincenzo A, Scaglione G, Morrone S, Finello V, Fagioli S, Castaldo F, Sanz JM, Sergi D, Passaro A. Ceramides as Emerging Players in Cardiovascular Disease: Focus on Their Pathogenetic Effects and Regulation by Diet. Adv Nutr 2024; 15:100252. [PMID: 38876397 PMCID: PMC11263787 DOI: 10.1016/j.advnut.2024.100252] [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: 02/27/2024] [Revised: 05/16/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024] Open
Abstract
Impaired lipid metabolism is a pivotal driver of cardiovascular disease (CVD). In this regard, the accumulation of ceramides within the circulation as well as in metabolically active tissues and atherosclerotic plaques is a direct consequence of derailed lipid metabolism. Ceramides may be at the nexus between impaired lipid metabolism and CVD. Indeed, although on one hand ceramides have been implicated in the pathogenesis of CVD, on the other specific ceramide subspecies have also been proposed as predictors of major adverse cardiovascular events. This review will provide an updated overview of the role of ceramides in the pathogenesis of CVD, as well as their pathogenetic mechanisms of action. Furthermore, the manuscript will cover the importance of ceramides as biomarkers to predict cardiovascular events and the role of diet, both in terms of nutrients and dietary patterns, in modulating ceramide metabolism and homeostasis.
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Affiliation(s)
- Riccardo Spaggiari
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Sharon Angelini
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Alessandra Di Vincenzo
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Gerarda Scaglione
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Sara Morrone
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Veronica Finello
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Sofia Fagioli
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Fabiola Castaldo
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Juana M Sanz
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
| | - Domenico Sergi
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy.
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, Ferrara, Italy
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Tan Z, Shen J, Huang Y, Li J, Ding M, Sun A, Hong J, Yang Y, He S, Zhu X, Luo R. Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization. Front Endocrinol (Lausanne) 2024; 15:1398600. [PMID: 39006368 PMCID: PMC11239382 DOI: 10.3389/fendo.2024.1398600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 06/11/2024] [Indexed: 07/16/2024] Open
Abstract
Background Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (β=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (β=-0.127), showed an indirect effect on infertility mediated by SUA (β=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.
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Affiliation(s)
- Zilong Tan
- Department of Urology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jianwu Shen
- Department of Urology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Urology, Qinghai Hospital of Traditional Chinese Medicine, Xining, China
| | - Yuxiao Huang
- Department of Gynecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junru Li
- Department of Internal Medicine, Qinghai Hospital of Traditional Chinese Medicine, Xining, China
| | - Mengdi Ding
- Department of Urology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Aochuan Sun
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Hong
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yan Yang
- Department of Critical Care Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Sheng He
- The First Clinical Medical College, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Xueying Zhu
- Department of Gynecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ran Luo
- Department of Gynecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Del Pozo Iribarren R, Mardones L, Villagrán M, Muñoz K, Troncoso L, Mellado M, Muñoz M. Effect of various dietary fructose concentrations on the gallstone formation process in mice. NUTR HOSP 2024; 41:194-201. [PMID: 37705438 DOI: 10.20960/nh.04610] [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] [Indexed: 09/15/2023] Open
Abstract
Introduction Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds to biliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consuming diets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or 70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levels were analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only at very high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cholesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differences in the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8) no change in biliary lipid concentrations or in micellar and vesicular phospholipids. Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructose apparently does not alter the gallstone formation process in our experimental model.
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Affiliation(s)
| | - Lorena Mardones
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
| | - Marcelo Villagrán
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
| | - Katia Muñoz
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
| | - Luciano Troncoso
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
| | - Maximiliano Mellado
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
| | - Mirna Muñoz
- Department of Basic Science. Facultad de Medicina. Universidad Católica de la Santísima Concepción
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Kubacka M, Nowak B, Zadrożna M, Szafarz M, Latacz G, Marona H, Sapa J, Mogilski S, Bednarski M, Kotańska M. Manifestations of Liver Impairment and the Effects of MH-76, a Non-Quinazoline α1-Adrenoceptor Antagonist, and Prazosin on Liver Tissue in Fructose-Induced Metabolic Syndrome. Metabolites 2023; 13:1130. [PMID: 37999226 PMCID: PMC10672990 DOI: 10.3390/metabo13111130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/25/2023] Open
Abstract
Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications.
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Affiliation(s)
- Monika Kubacka
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland; (M.K.); (J.S.); (S.M.)
| | - Barbara Nowak
- Department of Cytobiology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland; (B.N.); (M.Z.)
| | - Monika Zadrożna
- Department of Cytobiology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland; (B.N.); (M.Z.)
| | - Małgorzata Szafarz
- Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland;
| | - Gniewomir Latacz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland;
| | - Henryk Marona
- Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland;
| | - Jacek Sapa
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland; (M.K.); (J.S.); (S.M.)
| | - Szczepan Mogilski
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland; (M.K.); (J.S.); (S.M.)
| | - Marek Bednarski
- Department of Pharmacological Screening, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland;
| | - Magdalena Kotańska
- Department of Pharmacological Screening, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Krakow, Poland;
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Xiao Z, Liu M, Yang F, Liu G, Liu J, Zhao W, Ma S, Duan Z. Programmed cell death and lipid metabolism of macrophages in NAFLD. Front Immunol 2023; 14:1118449. [PMID: 36742318 PMCID: PMC9889867 DOI: 10.3389/fimmu.2023.1118449] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has now become the leading chronic liver disease worldwide with lifestyle changes. This may lead to NAFLD becoming the leading cause of end-stage liver disease in the future. To date, there are still no effective therapeutic drugs for NAFLD. An in-depth exploration of the pathogenesis of NAFLD can help to provide a basis for new therapeutic agents or strategies. As the most important immune cells of the liver, macrophages play an important role in the occurrence and development of liver inflammation and are expected to become effective targets for NAFLD treatment. Programmed cell death (PCD) of macrophages plays a regulatory role in phenotypic transformation, and there is also a certain connection between different types of PCD. However, how PCD regulates macrophage polarization has still not been systematically elucidated. Based on the role of lipid metabolic reprogramming in macrophage polarization, PCD may alter the phenotype by regulating lipid metabolism. We reviewed the effects of macrophages on inflammation in NAFLD and changes in their lipid metabolism, as well as the relationship between different types of PCD and lipid metabolism in macrophages. Furthermore, interactions between different types of PCD and potential therapeutic agents targeting of macrophages PCD are also explored.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Minghao Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Guangwei Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Jiangkai Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Wenxia Zhao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China,*Correspondence: Suping Ma, ; Zhongping Duan,
| | - Zhongping Duan
- Beijing Institute of Hepatology, Beijing Youan Hospital Capital Medical University, Beijing, China,*Correspondence: Suping Ma, ; Zhongping Duan,
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Bentanachs R, Velázquez AM, Sánchez RM, Alegret M, Laguna JC, Roglans N. Bempedoic acid as a PPARα activator: new perspectives for hepatic steatosis treatment in a female rat experimental model. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2022; 34:57-67. [PMID: 34887111 DOI: 10.1016/j.arteri.2021.09.004] [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: 06/04/2021] [Revised: 07/19/2021] [Accepted: 09/18/2021] [Indexed: 06/13/2023]
Abstract
INTRODUCTION In its initial stages, nonalcoholic fatty liver disease presents hypertriglyceridemia and accumulation of lipids in the liver (hepatic steatosis). Bempedoic acid is an ATP:citrate lyase inhibitor that promotes a dual inhibition of the synthesis of cholesterol and fatty acids. However, its effect in the prevention / treatment of hepatic steatosis and hypertriglyceridemia has not been investigated. The aim of our work has been to elucidate whether bempedoic acid, through a mechanism other than ATP:citrate lyase inhibition, reverses these metabolic alterations. EXPERIMENTAL DESIGN The study was carried out in female Sprague-Dawley rats fed, for three months, with a high fat diet supplemented with fructose (10% w/v) in drinking water. During the last month, bempedoic acid (30mg/kg/day) was administered to a group of animals. Zoometric and plasmatic parameters were analyzed, gene and protein expression analysis were performed in liver samples and PPAR-PPRE binding activity was determined. RESULTS Our interventional model developed hepatic steatosis and hypertriglyceridemia. Despite an increase in total caloric intake, there was no increase in body weight of the animals. The administration of bempedoic acid significantly reduced hepatic steatosis and promoted a marked hepatocyte hypertrophy. There was a 66% increase in the liver weight of the animals treated with the drug that was not accompanied by modifications in the markers of inflammation, oxidative stress, or endoplasmic reticulum stress. Bempedoic acid activated the peroxisome proliferator activated nuclear receptor (PPARα) and its target genes. CONCLUSIONS Bempedoic acid could be an effective therapy for the treatment of fatty liver and associated cardiovascular risk. Bempedoic acid has other mechanisms of action besides the inhibition of ATP: citrate lyase, such as the activation of PPARα, which could explain the reduction in hepatic steatosis and the increase in liver weight observed in animals treated with the drug.
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Affiliation(s)
- Roger Bentanachs
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España
| | - Ana Magdalena Velázquez
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España
| | - Rosa María Sánchez
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, España; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, España
| | - Marta Alegret
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, España; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, España
| | - Juan Carlos Laguna
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, España; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, España
| | - Núria Roglans
- Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, España; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, España.
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Wu F, Xu L, Tu Y, Cheung OK, Szeto LL, Mok MT, Yang W, Kang W, Cao Q, Lai PB, Chan SL, Tan P, Sung JJ, Yip KY, Cheng AS, To KF. Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis. Cancer Lett 2021; 525:115-130. [PMID: 34736960 DOI: 10.1016/j.canlet.2021.10.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.
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Affiliation(s)
- Feng Wu
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Liangliang Xu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yalin Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Otto Kw Cheung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lemuel Lm Szeto
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Myth Ts Mok
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Qin Cao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Bs Lai
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Stephen L Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
| | - Joseph Jy Sung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kevin Y Yip
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Alfred Sl Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Ka F To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Hu J, Xu W, Yang H, Mu L. Uric acid participating in female reproductive disorders: a review. Reprod Biol Endocrinol 2021; 19:65. [PMID: 33906696 PMCID: PMC8077923 DOI: 10.1186/s12958-021-00748-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/18/2021] [Indexed: 12/21/2022] Open
Abstract
Uric acid (UA) is the end metabolic product of purine metabolism. Early on, UA was considered to be a metabolite with a certain antioxidant capacity. As research has progressed, other properties of UA have been explored, and its association with many diseases has been found. The association between UA and kidney disease and cardiovascular disease is well established; however, there is still a paucity of reviews on the association between UA and the female reproductive system. An increasing number of epidemiological studies have shown elevated serum UA levels in patients with polycystic ovary syndrome (PCOS), endometriosis, etc. Additionally, serum UA can be used as a predictor of pregnancy complications and adverse foetal outcomes. An increasing number of animal experiments and clinical studies have revealed possible mechanisms related to the involvement of UA in certain female reproductive disorders: oxidative stress, chronic inflammation, mitochondrial dysfunction, etc. This article reviews the current mainstream mechanisms regarding the pathogenesis of UA and the role of UA in certain specific female reproductive disorders (direct involvement in the development of certain diseases or enhancement of other risk factors) in the hope of contributing to clinical prevention, diagnosis, treatment and improvement in prognosis.
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Affiliation(s)
- Junhao Hu
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, No.96 Fuxue Road, 325000, Wenzhou, People's Republic of China
| | - Wenyi Xu
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, No.96 Fuxue Road, 325000, Wenzhou, People's Republic of China
| | - Haiyan Yang
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, No.96 Fuxue Road, 325000, Wenzhou, People's Republic of China.
| | - Liangshan Mu
- School of Medicine, Zhejiang University, No.866 Yuhantang Road, 310058, Hangzhou, People's Republic of China.
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10
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Pathobiological and molecular connections involved in the high fructose and high fat diet induced diabetes associated nonalcoholic fatty liver disease. Inflamm Res 2020; 69:851-867. [DOI: 10.1007/s00011-020-01373-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/22/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022] Open
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11
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Xu Y, Wu Y, Xiong Y, Tao J, Pan T, Tan S, Gao G, Chen Y, Abbas N, Getachew A, Zhuang Y, You K, Yang F, Li YX. Ascorbate protects liver from metabolic disorder through inhibition of lipogenesis and suppressor of cytokine signaling 3 (SOCS3). Nutr Metab (Lond) 2020; 17:17. [PMID: 32158492 PMCID: PMC7057613 DOI: 10.1186/s12986-020-0431-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 01/20/2020] [Indexed: 12/28/2022] Open
Abstract
Background Fatty liver is a reversible status, but also an origin stage to develop to other metabolic syndromes, such as diabetes and heart disease that threatens public health worldwide. Ascorbate deficiency is reported to be correlated with increasing risks for metabolic syndromes, but whether ascorbate has a therapeutic effect is unknown. Here, we investigated if ascorbate treatment alone could work on protecting from the development of steatosis and mechanisms beyond. Methods Guinea pigs were fed with a chow diet or a high palm oil diet (HPD) respectively. HPD induced animals were administered different concentrations of ascorbate in different time intervals through water. Besides, hepatocyte-like cells derived from human embryonic stem cells and HepG2 cells were treated with palmitic acid (PA) to induce lipid accumulation for molecular mechanism study. Results We find that ascorbate rescues HPD and PA induced steatosis and insulin tolerance in vivo and in vitro. We demonstrate that ascorbate changes cellular lipid profiles via inhibits lipogenesis, and inhibits the expression of SOCS3 via STAT3, thus enhances insulin signal transduction. Overexpression of SOCS3 abolishes the ascorbate rescue effects on insulin signal and lipid accumulation in hepatic cells. Conclusions Ascorbate ameliorates hepatic steatosis and improves insulin sensitivity through inhibiting lipogenesis and SOCS3.
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Affiliation(s)
- Yingying Xu
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China
| | - Yuhang Wu
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China
| | - Yue Xiong
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Jiawang Tao
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Tingcai Pan
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Shenglin Tan
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Ge Gao
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China
| | - Yan Chen
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,4Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, GIBH, CAS, Guangzhou, 510000 China.,5Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Nasir Abbas
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Anteneh Getachew
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,3University of Chinese Academy of Sciences, Beijing, 100000 China
| | - Yuanqi Zhuang
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China
| | - Kai You
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China
| | - Fan Yang
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,4Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, GIBH, CAS, Guangzhou, 510000 China.,5Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Yin-Xiong Li
- 1Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510000 China.,2Guangdong Provincial Key Laboratory of Biocomputing, GIBH, CAS, Guangzhou, 510000 China.,4Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, GIBH, CAS, Guangzhou, 510000 China.,5Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
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12
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Walker ME, Xanthakis V, Moore LL, Vasan RS, Jacques PF. Cumulative sugar-sweetened beverage consumption is associated with higher concentrations of circulating ceramides in the Framingham Offspring Cohort. Am J Clin Nutr 2020; 111:420-428. [PMID: 31826243 PMCID: PMC6997085 DOI: 10.1093/ajcn/nqz257] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 09/19/2019] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Ceramides have been implicated in the pathogenesis of type 2 diabetes and cardiovascular disease. Limited data exist on how habitual dietary intake of foods that can alter hepatic lipid metabolism may influence circulating ceramide concentrations. OBJECTIVES We investigated the cross-sectional association of cumulative sugar-sweetened beverage (SSB) consumption with concentrations of 3 circulating ceramides and ceramide ratios. METHODS We examined participants from the Framingham Heart Study's Offspring Cohort who had 3 ceramides measured (n = 1561, mean age 66 y, 59% women). SSB consumption was measured 4 times over ∼14 y. Participants were categorized by cumulative SSB intake as nonconsumers (0 to <1 SSB serving/mo) and occasional (1 SSB serving/mo to <1 serving/wk), frequent (1 SSB serving/wk to <1 serving/d), and daily (≥1 SSB serving/d) consumers. Multivariable linear regression models were used to relate cumulative SSB consumption (independent variable) to blood concentrations of ceramides (C16:0, C22:0, and C24:0) and ceramide ratios (C22:0/C16:0 and C24:0/C16:0). RESULTS In adjusted models, more frequent cumulative SSB consumption was positively associated with concentrations of the C16:0 and C22:0 ceramides (Ptrend < 0.05). Compared with nonconsumers, daily consumers had 0.01 μg/mL (95% CI: 0.002, 0.017 µg/mL) and 0.06 µg/mL (95% CI: 0.018, 0.092 µg/mL) higher mean concentrations of the C16:0 and C22:0 ceramides, respectively. Results were consistent when modeling continuous cumulative SSB consumption per 1 serving/d. We observed effect modification by diabetes status in the relation between cumulative SSB consumption and concentrations of the C24:0 ceramide (Pinteraction = 0.014). In a stratified analysis, more frequent cumulative SSB consumption was positively associated with concentrations of the C24:0 ceramide only in individuals with prediabetes or diabetes (Ptrend = 0.001). CONCLUSIONS Our study raises the possibility that higher concentrations of distinct ceramide species, previously associated with adverse metabolic health, may be one mechanism by which SSB consumption contributes to higher risk of cardiometabolic diseases.
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Affiliation(s)
- Maura E Walker
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Vanessa Xanthakis
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA,Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA,Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
| | - Lynn L Moore
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Ramachandran S Vasan
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA,Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA,Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Paul F Jacques
- Nutritional Epidemiology, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA,Address correspondence to PFJ (e-mail: )
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13
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Mohamad HE, Asker ME, Keshawy MM, Abdel Aal SM, Mahmoud YK. Infliximab ameliorates tumor necrosis factor-alpha exacerbated renal insulin resistance induced in rats by regulating insulin signaling pathway. Eur J Pharmacol 2020; 872:172959. [PMID: 32004528 DOI: 10.1016/j.ejphar.2020.172959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 12/17/2022]
Abstract
Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1β and 6 (Il-1β, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.
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Affiliation(s)
- Hoda E Mohamad
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Mervat E Asker
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Mohammed M Keshawy
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Ismailia, 41522, Suez Canal University, Egypt
| | - Sara M Abdel Aal
- Department of Histology& Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Yasmin K Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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14
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Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, Kahn CR. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 2020; 57:308-322. [PMID: 31935149 DOI: 10.1080/10408363.2019.1711360] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance via complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance.
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Affiliation(s)
- Samir Softic
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children's Hospital, Lexington, KY, USA.,Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Kimber L Stanhope
- Department of Molecular Biosciences, University of California, Davis, Davis, CA, USA
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.,The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, CO, USA
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, CO, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
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15
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Softic S, Meyer JG, Wang GX, Gupta MK, Batista TM, Lauritzen HPMM, Fujisaka S, Serra D, Herrero L, Willoughby J, Fitzgerald K, Ilkayeva O, Newgard CB, Gibson BW, Schilling B, Cohen DE, Kahn CR. Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins. Cell Metab 2019; 30:735-753.e4. [PMID: 31577934 PMCID: PMC7816129 DOI: 10.1016/j.cmet.2019.09.003] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/06/2019] [Accepted: 09/05/2019] [Indexed: 01/25/2023]
Abstract
Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on hepatic mitochondrial function and fatty acid oxidation. This is mediated via three different nodes of regulation, including differential effects on malonyl-CoA levels, effects on mitochondrial size/protein abundance, and acetylation of mitochondrial proteins. HFD- and HFD plus fructose-fed mice have decreased CTP1a activity, the rate-limiting enzyme of fatty acid oxidation, whereas knockdown of fructose metabolism increases CPT1a and its acylcarnitine products. Furthermore, fructose-supplemented HFD leads to increased acetylation of ACADL and CPT1a, which is associated with decreased fat metabolism. In summary, dietary fructose, but not glucose, supplementation of HFD impairs mitochondrial size, function, and protein acetylation, resulting in decreased fatty acid oxidation and development of metabolic dysregulation.
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Affiliation(s)
- Samir Softic
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, Nutrition, Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children's Hospital, Lexington, KY 40506, USA.
| | - Jesse G Meyer
- Chemistry & Mass Spectrometry, Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Guo-Xiao Wang
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Manoj K Gupta
- Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Thiago M Batista
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Hans P M M Lauritzen
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Shiho Fujisaka
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; First Department of Internal Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Dolors Serra
- School of Pharmacy, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Laura Herrero
- School of Pharmacy, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | | | | | - Olga Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology & Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology & Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USA
| | - Bradford W Gibson
- Chemistry & Mass Spectrometry, Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Birgit Schilling
- Chemistry & Mass Spectrometry, Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - David E Cohen
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College New York, New York, NY 10021, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
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16
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Rai AK, Jaiswal N, Maurya CK, Sharma A, Ahmad I, Ahmad S, Gupta AP, Gayen JR, Tamrakar AK. Fructose-induced AGEs-RAGE signaling in skeletal muscle contributes to impairment of glucose homeostasis. J Nutr Biochem 2019; 71:35-44. [PMID: 31272030 DOI: 10.1016/j.jnutbio.2019.05.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 05/22/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023]
Abstract
Increased fructose intake has been linked to the development of dyslipidemia, obesity and impaired glucose tolerance. Due to its specific metabolic fate, fructose impairs normal lipid and carbohydrate metabolism and facilitates the non-enzymatic glycation reaction leading to enhanced accumulation of advanced glycation end products (AGEs). However, the formation of fructose-AGEs under in vivo setup and its tissue specific accumulation is less explored. Here, we investigated the impact of high fructose on AGEs accumulation in skeletal muscle and its causal role in impaired glucose homeostasis. In L6 rat skeletal muscle cells, chronic exposure to fructose induced AGEs accumulation and the cellular level of the receptor for AGEs (RAGE) and the effect was prevented by pharmacological inhibition of glycation. Under in vivo settings, Sprague Dawley rats exposed to 20% fructose in drinking water for 16 weeks, displayed increased fasting glycemia, impaired glucose tolerance, decreased skeletal muscle Akt (Ser-473) phosphorylation, and enhanced triglyceride levels in serum, liver and gastrocnemius muscle. We also observed a high level of AGEs in serum and gastrocnemius muscle of fructose-supplemented animals, associated with methylglyoxal accumulation and up regulated expression of RAGE in gastrocnemius muscle. Treatment with aminoguanidine inhibited fructose-induced AGEs accumulation and normalized the expression of RAGE and Dolichyl-Diphosphooligosaccharide-Protein Glycosyltransferase (DDOST) in gastrocnemius muscle. Inhibition of AGEs-RAGE axis counteracted fructose-mediated glucose intolerance without affecting energy metabolism. These data reveal diet-derived AGEs accumulation in skeletal muscle and the implication of tissue specific AGEs in metabolic derangement, that may open new perspectives in pathogenic mechanisms and management of metabolic diseases.
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Affiliation(s)
- Amit K Rai
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Natasha Jaiswal
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Chandan K Maurya
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Aditya Sharma
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Ishbal Ahmad
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Shadab Ahmad
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031; Academy of Scientific and Innovative Research (AcSIR), New Delhi-201002, India
| | - Anand P Gupta
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Jiaur R Gayen
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow-226031
| | - Akhilesh K Tamrakar
- Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031; Academy of Scientific and Innovative Research (AcSIR), New Delhi-201002, India.
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17
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Di Ciaula A, Garruti G, Frühbeck G, De Angelis M, de Bari O, Wang DQH, Lammert F, Portincasa P. The Role of Diet in the Pathogenesis of Cholesterol Gallstones. Curr Med Chem 2019; 26:3620-3638. [PMID: 28554328 PMCID: PMC8118138 DOI: 10.2174/0929867324666170530080636] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/03/2017] [Accepted: 03/16/2017] [Indexed: 02/06/2023]
Abstract
Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.
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Affiliation(s)
| | - Gabriella Garruti
- Department of Emergency and Organ Transplants, Section of Endocrinology, Andrology and Metabolic Diseases, University of Bari Medical School, Bari, Italy
| | - Gema Frühbeck
- Dept Endocrinology and Nutrition, University of Navarra Medical School, Pamplona, Spain
| | - Maria De Angelis
- Department of Soil, Plant and Food Science, Department of Biomedical Sciences and Human Oncology
| | - Ornella de Bari
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology
| | - David Q.-H. Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg, Germany
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology
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18
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Preconditioning lessens high fat induced metabolic syndrome along with markers of increased metabolic capacity in muscle and adipose tissue. Biosci Rep 2018; 38:BSR20181873. [PMID: 30455397 PMCID: PMC6294636 DOI: 10.1042/bsr20181873] [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: 08/08/2018] [Revised: 11/08/2018] [Accepted: 11/11/2018] [Indexed: 12/02/2022] Open
Abstract
Postnatal overconsumption of fat is believed to increase the susceptibility to metabolic disease in the later life. Here we examined whether prior exposure to high fat (HF) in the adulthood may also accelerate the development of metabolic disorders in mice. Adult mice (12 weeks) were pre-exposed to two episodes of an HF diet each for 2 weeks followed by 2 weeks of washout with a low-fat diet. The mice were then fed the same HF diet for 6 weeks. Unexpectedly, prior exposures to HF diet significantly alleviated body weight gain, visceral adiposity and glucose/insulin intolerance during the period of last HF feeding. These protective effects were evident without changing calorie intake and were specific for HF, but not high fructose (HFru) diet. Following the HF prior exposures was increases in plasma fibroblast growth factor 21 (FGF21), the expressions of phospho-AMP-activated protein kinase (pAMPK), mitochondrial complex II and the expression of uncoupling protein (UCP) 3 in muscle and UCP1 and Sirtuin 1 (SIRT1) in adipose tissue. However, in the liver there was no significant change in pAMPK, SIRT1 expression or the capacity of glucose production. These findings indicated that, instead of exacerbating metabolic conditions, prior exposures to HF diet lead to the preconditioning against subsequent overload of HF, possibly involving FGF21-associated enhancement of markers for metabolic capacity in muscle and adipose tissue. This paradoxical phenomenon may offer a unique paradigm to identify factors and explore dietary ingredients with beneficial effects for the control of the metabolic syndrome in humans.
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19
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Sangüesa G, Roglans N, Montañés JC, Baena M, Velázquez AM, Sánchez RM, Alegret M, Laguna JC. Chronic Liquid Fructose, but not Glucose, Supplementation Selectively Induces Visceral Adipose Tissue Leptin Resistance and Hypertrophy in Female Sprague-Dawley Rats. Mol Nutr Food Res 2018; 62:e1800777. [DOI: 10.1002/mnfr.201800777] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/17/2018] [Indexed: 12/31/2022]
Affiliation(s)
- Gemma Sangüesa
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
| | - Núria Roglans
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn); Madrid Spain
| | - José Carlos Montañés
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
| | - Miguel Baena
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
| | - Ana Magdalena Velázquez
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
| | - Rosa María Sánchez
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn); Madrid Spain
| | - Marta Alegret
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn); Madrid Spain
| | - Juan Carlos Laguna
- Department of Pharmacology; Toxicology and Therapeutic Chemistry; School of Pharmacy and Food Science; University of Barcelona; 08028 Barcelona Spain
- Institute of Biomedicine; University of Barcelona; 08028 Barcelona Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn); Madrid Spain
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20
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Mathews AT, Famodu OA, Olfert MD, Murray PJ, Cuff CF, Downes MT, Haughey NJ, Colby SE, Chantler PD, Olfert IM, McFadden JW. Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study. Physiol Rep 2018; 5:5/13/e13329. [PMID: 28694327 PMCID: PMC5506522 DOI: 10.14814/phy2.13329] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 05/29/2017] [Indexed: 12/14/2022] Open
Abstract
The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual's risk for type 2 diabetes, nonalcoholic fatty liver disease, low‐grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free‐living fruit and vegetable intervention on overall metabolic health, circulating ceramide supply, and inflammatory status in young adults. We discovered that adoption of the recommended DGA for fruit and vegetable intake for 8 weeks decreased waist circumference, systolic blood pressure, and circulating cholesterol. Lipidomics analysis revealed that nutritional intervention can lower circulating ceramides, including C24:0 ceramide, a known inhibitor of insulin signaling. Unexpectedly, we observed an increase in C16:0 ceramide, suggesting that this form of ceramide in circulation is not associated with metabolic disease in humans. We also observed an improved inflammatory status with enhanced fruit and vegetable intake that was correlated with ceramide concentrations. These data suggest that adopting the recommended DGA is associated with a reduction of many, but not all, ceramide species and may help to prevent or mitigate MetS. Future research needs to assess whether the ceramide‐lowering ability of nutritional intervention is associated with reduced risk of developing metabolic disease.
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Affiliation(s)
- Alice T Mathews
- Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, West Virginia
| | - Oluremi A Famodu
- Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, West Virginia
| | - Melissa D Olfert
- Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, West Virginia.,West Virginia Clinical and Translational Science Institute, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia
| | - Pamela J Murray
- West Virginia Clinical and Translational Science Institute, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia.,Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Christopher F Cuff
- West Virginia Clinical and Translational Science Institute, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia.,Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Marianne T Downes
- Division of Medical Laboratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Norman J Haughey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sarah E Colby
- Department of Nutrition Science, University of Tennessee, Knoxville, Tennessee
| | - Paul D Chantler
- West Virginia Clinical and Translational Science Institute, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia.,Department of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - I Mark Olfert
- West Virginia Clinical and Translational Science Institute, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia.,Department of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Joseph W McFadden
- Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, West Virginia
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21
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High fructose diet-induced metabolic syndrome: Pathophysiological mechanism and treatment by traditional Chinese medicine. Pharmacol Res 2018; 130:438-450. [PMID: 29471102 DOI: 10.1016/j.phrs.2018.02.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/09/2018] [Accepted: 02/14/2018] [Indexed: 02/08/2023]
Abstract
Fructose is a natural monosaccharide broadly used in modern society. Over the past few decades, epidemiological studies have demonstrated that high fructose intake is an etiological factor of metabolic syndrome (MetS). This review highlights research advances on fructose-induced MetS, especially the underlying pathophysiological mechanism as well as pharmacotherapy by traditional Chinese medicine (TCM), using the PubMed, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal and Wanfang Data. This review focuses on de novo lipogenesis (DNL) and uric acid (UA) production, two unique features of fructolysis different from glucose glycolysis. High level of DNL and UA production can result in insulin resistance, the key pathological event in developing MetS, mostly through oxidative stress and inflammation. Some other pathologies like the disturbance in brain and gut microbiota in the development of fructose-induced MetS in the past years, are also discussed. In management of MetS, TCM is an excellent representative in alternative and complementary medicine with a complete theory system and substantial herbal remedies. TCMs against MetS or MetS components, including Chinese patent medicines, TCM compound formulas, single TCM herbs and active compounds of TCM herbs, are reviewed on their effects and molecular mechanisms. TCMs with hypouricemic activity, which specially target fructose-induced MetS, are highlighted. And new technologies and strategies (such as high-throughput assay and systems biology) in this field are further discussed. In summary, fructose-induced MetS is a multifactorial disorder with the underlying complex mechanisms. Current clinical and pre-clinical evidence supports the potential of TCMs in management of MetS. Additionally, TCMs may show some advantages against complex MetS as their holistic feature through multiple target actions. However, further work is needed to confirm the effectivity and safety of TCMs by high-standard clinical trials, clarify the molecular mechanisms, and develop new anti-MetS drugs by development and application of optimized and feasible strategies and methods.
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22
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Obesity linking to hepatocellular carcinoma: A global view. Biochim Biophys Acta Rev Cancer 2018; 1869:97-102. [PMID: 29366974 DOI: 10.1016/j.bbcan.2017.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 12/20/2017] [Accepted: 12/20/2017] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is the commonest primary liver cancer and the second leading cause of cancer death worldwide. Obesity is rapidly becoming pandemic and associated with increased carcinogenesis. In this review, we describe the obesity-related factors that influence the development of HCC. We provide evidence of strong links between neural regulation, endocrine and HCC in obesity. We discuss recent advances in our understanding of how adipose tissue alters hepatic metabolism and immune response in HCC development through inter-organ communication. Taken together, our review aims to provides a concise and up-to date summary about the connection between obesity and HCC, with emphasis on the opportunities for effective strategies in preventing the development of HCC in obese individuals.
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23
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Elmowafy M, Ibrahim HM, Ahmed MA, Shalaby K, Salama A, Hefesha H. Atorvastatin-loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks. Drug Deliv 2017; 24:932-941. [PMID: 28617150 PMCID: PMC8241136 DOI: 10.1080/10717544.2017.1337823] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Atorvastatin (AT) is a widely used lipid-regulating drug to reduce cholesterol and triglycerides. Its poor aqueous solubility and hepatic metabolism require development of drug delivery systems able to improve its solubility and bypass hepatic effect. For this purpose, atorvastatin nanostructured lipid carriers (AT-NLCs) were prepared and characterized. AT-NLCs were prepared by emulsification using high-speed homogenization followed by ultrasonication. The prepared NLCs showed particle size between 162.5 ± 12 and 865.55 ± 28 nm while zeta potential values varied between −34 ± 0.29 and −23 ± 0.36 mV. They also showed high encapsulation efficiency (>87%) and amorphous state of the drug in lipid matrix. Pharmacokinetic parameters of optimized formulation (NLC-1; composed of 2% Gelucire® 43/01, 8% Capryol® PGMC, 2% Pluronic®F68 and 0.5% lecithin) revealed 3.6- and 2.1-fold increase in bioavailability as compared to atorvastatin suspension and commercial product (Lipitor®), respectively. Administration of NLC-1 led to significant reduction (p < .05) in the rats’ serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and significant increase in high-density lipoprotein (HDL). This improvement was confirmed histologically by minimizing the associated hepatic steatosis. These investigations demonstrated the superiority of NLCs for improvement of oral bioavailability and in vivo performance of AT.
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Affiliation(s)
- Mohammed Elmowafy
- a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Hany M Ibrahim
- a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Mohammed A Ahmed
- b Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Cairo University , Cairo , Egypt
| | - Khaled Shalaby
- a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Ayman Salama
- a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Hossam Hefesha
- a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
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24
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Zhang DM, Jiao RQ, Kong LD. High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions. Nutrients 2017; 9:E335. [PMID: 28353649 PMCID: PMC5409674 DOI: 10.3390/nu9040335] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/15/2017] [Accepted: 03/24/2017] [Indexed: 02/06/2023] Open
Abstract
High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.
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Affiliation(s)
- Dong-Mei Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
| | - Rui-Qing Jiao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
| | - Ling-Dong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
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25
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Sangüesa G, Shaligram S, Akther F, Roglans N, Laguna JC, Rahimian R, Alegret M. Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats. Am J Physiol Heart Circ Physiol 2016; 312:H289-H304. [PMID: 27923787 DOI: 10.1152/ajpheart.00339.2016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 10/24/2016] [Accepted: 11/07/2016] [Indexed: 12/31/2022]
Abstract
High consumption of simple sugars causes adverse cardiometabolic effects. We investigated the mechanisms underlying the metabolic and vascular effects of glucose or fructose intake and determined whether these effects are exclusively related to increased calorie consumption. Female Sprague-Dawley rats were supplemented with 20% wt/vol glucose or fructose for 2 mo, and plasma analytes and aortic response to vasodilator and vasoconstrictor agents were determined. Expression of molecules associated with lipid metabolism, insulin signaling, and vascular response were evaluated in hepatic and/or aortic tissues. Caloric intake was increased in both sugar-supplemented groups vs. control and in glucose- vs. fructose-supplemented rats. Hepatic lipogenesis was induced in both groups. Plasma triglycerides were increased only in the fructose group, together with decreased expression of carnitine palmitoyltransferase-1A and increased microsomal triglyceride transfer protein expression in the liver. Plasma adiponectin and peroxisome proliferator-activated receptor (PPAR)-α expression was increased only by glucose supplementation. Insulin signaling in liver and aorta was impaired in both sugar-supplemented groups, but the effect was more pronounced in the fructose group. Fructose supplementation attenuated aortic relaxation response to a nitric oxide (NO) donor, whereas glucose potentiated it. Phenylephrine-induced maximal contractions were reduced in the glucose group, which could be related to increased endothelial NO synthase (eNOS) phosphorylation and subsequent elevated basal NO in the glucose group. In conclusion, despite higher caloric intake in glucose-supplemented rats, fructose caused worse metabolic and vascular responses. This may be because of the elevated adiponectin level and the subsequent enhancement of PPARα and eNOS phosphorylation in glucose-supplemented rats. NEW & NOTEWORTHY This is the first study comparing the effects of glucose and fructose consumption on metabolic factors and aortic function in female rats. Our results show that, although total caloric consumption was higher in glucose-supplemented rats, fructose ingestion had a greater impact in inducing metabolic and aortic dysfunction.
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Affiliation(s)
- Gemma Sangüesa
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Sonali Shaligram
- Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California
| | - Farjana Akther
- Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California
| | - Núria Roglans
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Madrid, Spain
| | - Juan C Laguna
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Madrid, Spain
| | - Roshanak Rahimian
- Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California
| | - Marta Alegret
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; .,Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Madrid, Spain
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26
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Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016; 65:1049-61. [PMID: 26997538 PMCID: PMC4931958 DOI: 10.1016/j.metabol.2016.02.014] [Citation(s) in RCA: 409] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 02/05/2016] [Accepted: 02/23/2016] [Indexed: 12/21/2022]
Abstract
The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.
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Affiliation(s)
- Manoela Mota
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Bubu A Banini
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sophie C Cazanave
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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27
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Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Sci Rep 2016; 6:26149. [PMID: 27194405 PMCID: PMC4872141 DOI: 10.1038/srep26149] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 04/27/2016] [Indexed: 12/12/2022] Open
Abstract
Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.
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28
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Li X, Xu Z, Wang S, Guo H, Dong S, Wang T, Zhang L, Jiang Z. Emodin ameliorates hepatic steatosis through endoplasmic reticulum-stress sterol regulatory element-binding protein 1c pathway in liquid fructose-feeding rats. Hepatol Res 2016; 46:E105-17. [PMID: 26031413 DOI: 10.1111/hepr.12538] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 05/12/2015] [Accepted: 05/18/2015] [Indexed: 12/13/2022]
Abstract
AIM To investigate the effects of emodin on the treatment of non-alcoholic fatty liver in rats induced by liquid fructose-feeding in rats and the possible underlying mechanisms. METHODS Sprague-Dawley rats were divided into the control, fructose-feeding group, and three fructose-feeding groups treated with 40, 80 and 160 mg/kg emodin, respectively. After 4 weeks of feeding, liquid consumption, food intake, bodyweight, liver index, serum triglyceride (TG), glucose and aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), liver TG contents and histology features were examined. The hepatic expression of lipogenic and fatty acid oxidation key enzymes, and an upstream transcriptional factor, sterol regulatory element-binding protein 1c (SREBP1c) were determined. Glucose regulated protein 78 (GRP78), a liver endoplasmic reticulum stress (ERS) marker and the unfolded protein response (UPR) related proteins were also measured. RESULTS Emodin reduced bodyweight, liver index, serum TG levels of fructose-feeding rats with no significant difference in serum glucose, AST and ALT levels. Emodin improved hepatic steatosis by inhibiting SREBP1c activation and its target genes, and enhancing carnitine palmitoyltransferase 1 expression in fructose-feeding rats. Emodin resolved hepatic ERS and the UPR induced by liquid fructose in rats. CONCLUSION Emodin is capable of improving the lipid accumulation through the ERS-SREBP1c pathway in fructose-induced non-alcoholic fatty liver disease.
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Affiliation(s)
- Xiaojie Li
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China
| | - Zhimeng Xu
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China
| | - Shaojie Wang
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China
| | - Hongli Guo
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China
| | - Sizhe Dong
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China
| | - Tao Wang
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Nanjing, China
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China.,Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, Nanjing, China.,Jiangsu Center for Pharmacodynamics Research and Evaluation, Nanjing, China
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29
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Saran U, Humar B, Kolly P, Dufour JF. Hepatocellular carcinoma and lifestyles. J Hepatol 2016; 64:203-14. [PMID: 26341826 DOI: 10.1016/j.jhep.2015.08.028] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/19/2015] [Accepted: 08/24/2015] [Indexed: 12/31/2022]
Abstract
The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to non-alcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and non-alcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.
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Affiliation(s)
- Uttara Saran
- Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
| | - Bostjan Humar
- Department of Visceral & Transplantation Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Philippe Kolly
- Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland.
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Lima MLRP, Leite LHR, Gioda CR, Leme FOP, Couto CA, Coimbra CC, Leite VHR, Ferrari TCA. A Novel Wistar Rat Model of Obesity-Related Nonalcoholic Fatty Liver Disease Induced by Sucrose-Rich Diet. J Diabetes Res 2016; 2016:9127076. [PMID: 26788524 PMCID: PMC4691608 DOI: 10.1155/2016/9127076] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/11/2015] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not fully understood, and experimental models are an alternative to study this issue. We investigated the effects of a simple carbohydrate-rich diet on the development of obesity-related NAFLD and the impact of physical training on the metabolic abnormalities associated with this disorder. Sixty Wistar rats were randomly separated into experimental and control groups, which were fed with sucrose-enriched (18% simple carbohydrates) and standard diet, respectively. At the end of each experimental period (5, 10, 20, and 30 weeks), 6 animals from each group were sacrificed for blood tests and liver histology and immunohistochemistry. From weeks 25 to 30, 6 animals from each group underwent physical training. The experimental group animals developed obesity and NAFLD, characterized histopathologically by steatosis and hepatocellular ballooning, clinically by increased thoracic circumference and body mass index associated with hyperleptinemia, and metabolically by hyperglycemia, hyperinsulinemia, hypertriglyceridemia, increased levels of very low-density lipoprotein- (VLDL-) cholesterol, depletion of the antioxidants liver enzymes superoxide dismutase and catalase, and increased hepatic levels of malondialdehyde, an oxidative stress marker. Rats that underwent physical training showed increased high-density lipoprotein- (HDL-) cholesterol levels. In conclusion, a sucrose-rich diet induced obesity, insulin resistance, oxidative stress, and NAFLD in rats.
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Affiliation(s)
- Maria Luíza R. P. Lima
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena 190, 30130-100 Belo Horizonte, MG, Brazil
| | - Laura H. R. Leite
- Departamento de Fisiologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil
| | - Carolina R. Gioda
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Carreiros, 96203-900 Rio Grande, RS, Brazil
| | - Fabíola O. P. Leme
- Departamento de Veterinária Clínica e Cirúrgica, Escola de Veterinária, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil
| | - Claudia A. Couto
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena 190, 30130-100 Belo Horizonte, MG, Brazil
| | - Cândido C. Coimbra
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil
| | - Virginia H. R. Leite
- Departamento de Anatomia Patológica e Medicina Legal, Faculdade de Medicina, Universidade Federal de Minas Gerais, 30130-100 Belo Horizonte, MG, Brazil
| | - Teresa Cristina A. Ferrari
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena 190, 30130-100 Belo Horizonte, MG, Brazil
- *Teresa Cristina A. Ferrari:
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López-Rodríguez G, Osuna SK, García MG, Dieguez TS. Effects of dietary high fructose corn syrup on regulation of energy intake and leptin gene expression in rats. REV NUTR 2015. [DOI: 10.1590/1415-52732015000600003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE: To evaluate in Wistar rats the effect of chronic use of high fructose corn syrup on serum lipids, body weight, energy intake regulation, and expression of associated genes. METHODS: For 11 weeks, male rats were fed a standard diet with either water (control) or 15% high fructose corn syrup solution, or fed a high-fat diet. The rats' food intake and body weight were measured weekly. Expression of leptin and fatty acid synthase genes was quantified in their brain and adipose tissue upon sacrifice at age 119 days using real-time polymerase chain reaction. RESULTS: The intake of 15% high fructose corn syrup did not affect the rats' weight, only the rats on the high-fat diet gained significant weight. The rats in both diets had lower levels of leptin expression and high levels of fatty acid synthase in the brain, which were associated with high serum triglycerides. CONCLUSION: Fifteen percent high fructose corn syrup intake and the high-fat diet reduced leptin gene expression in the brain of Wistar rats, with differential effects on weight gain.
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Ge CX, Yu R, Xu MX, Li PQ, Fan CY, Li JM, Kong LD. Betaine prevented fructose-induced NAFLD by regulating LXRα/PPARα pathway and alleviating ER stress in rats. Eur J Pharmacol 2015; 770:154-64. [PMID: 26593707 DOI: 10.1016/j.ejphar.2015.11.043] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 12/28/2022]
Abstract
Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up-regulated hepatic expression of liver X receptor-alpha (LXRα) and peroxisome proliferator-activated receptor-alpha (PPARα), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1α, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase α, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRα and PPARα expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD.
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Affiliation(s)
- Chen-Xu Ge
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Rong Yu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Min-Xuan Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Pei-Qin Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Chen-Yu Fan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Jian-Mei Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
| | - Ling-Dong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
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Di Bartolomeo F, Van den Ende W. Fructose and Fructans: Opposite Effects on Health? PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2015; 70:227-37. [PMID: 25904233 DOI: 10.1007/s11130-015-0485-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Fructans are fructose-based oligo-and polysaccharides of natural origin. Fructan and fructose species are sometimes confused by the great public, although they clearly have different biochemical and physiological properties. This review discusses aspects of the use of fructose and fructans in foods in the context of human health, with possible differential effects on cellular autophagy in cells of the human body. Although there are uncertainties on the daily levels of ingested fructose to be considered harmful to human health, there is an emerging consensus on the benefits of the use of fructans in functional foods, sustaining health via direct immunomodulatory and antioxidant effects or through indirect, prebiotic mechanisms.
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Affiliation(s)
- Francesca Di Bartolomeo
- Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, 8010, Graz, Austria
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Mazzucco MB, Fornes D, Capobianco E, Higa R, Jawerbaum A, White V. Maternal saturated-fat-rich diet promotes leptin resistance in fetal liver lipid catabolism and programs lipid homeostasis impairments in the liver of rat offspring. J Nutr Biochem 2015; 27:61-9. [PMID: 26383539 DOI: 10.1016/j.jnutbio.2015.08.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 08/14/2015] [Accepted: 08/17/2015] [Indexed: 02/07/2023]
Abstract
We aimed to analyze if an overload of saturated fat in maternal diet induced lipid metabolic impairments in livers from rat fetuses that persist in the offspring and to identify potential mechanisms involving fetal leptin resistance. Female rats were fed either a diet enriched in 25% of saturated fat (SFD rats) or a regular diet (controls). Fetuses of 21days of gestation and offspring of 21 and 140days of age were obtained and plasma and liver were kept for further analysis. Livers from a group of control and SFD fetuses were cultured in the presence or absence of leptin. Leptin or vehicle was administered to control fetuses during the last days of gestation and, on day 21, fetal livers and plasma were obtained. Lipid levels were assessed by thin-layer chromatography and mRNA gene expression of CPT1, ACO and PPARα by RT-PCR. Liver lipid levels were increased and CPT1 and ACO were down-regulated in fetuses and offspring from SFD rats compared to controls. After the culture with leptin, control fetal livers showed increased ACO and CPT1 expression and decreased lipid levels, while fetal livers from SFD rats showed no changes. Fetal administration of leptin induced a decrease in ACO and no changes in CPT1 expression. In summary, our results suggest that a saturated fat overload in maternal diet induces fetal leptin resistance in liver lipid catabolism, which might be contributing to liver lipid alterations that are sustained in the offspring.
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Affiliation(s)
- María Belén Mazzucco
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina
| | - Daiana Fornes
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina
| | - Evangelina Capobianco
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina
| | - Romina Higa
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina
| | - Verónica White
- Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, School of Medicine, University of Buenos Aires, 1053 Buenos Aires, Argentina.
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Baena M, Sangüesa G, Hutter N, Sánchez RM, Roglans N, Laguna JC, Alegret M. Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:107-16. [DOI: 10.1016/j.bbalip.2014.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 10/14/2014] [Accepted: 11/04/2014] [Indexed: 01/13/2023]
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36
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Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight. Nutrients 2014; 6:5933-54. [PMID: 25533006 PMCID: PMC4277008 DOI: 10.3390/nu6125933] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 11/28/2014] [Accepted: 12/01/2014] [Indexed: 12/12/2022] Open
Abstract
Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved.
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37
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Sun RQ, Wang H, Zeng XY, Chan SMH, Li SP, Jo E, Leung SL, Molero JC, Ye JM. IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid. Biochim Biophys Acta Mol Basis Dis 2014; 1852:156-65. [PMID: 25458704 DOI: 10.1016/j.bbadis.2014.11.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 10/28/2014] [Accepted: 11/21/2014] [Indexed: 12/17/2022]
Abstract
The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding.
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Affiliation(s)
- Ruo-Qiong Sun
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Hao Wang
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Xiao-Yi Zeng
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Stanley M H Chan
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Song-Pei Li
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Eunjung Jo
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Sit-Lam Leung
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Juan C Molero
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia
| | - Ji-Ming Ye
- Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
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Li JM, Ge CX, Xu MX, Wang W, Yu R, Fan CY, Kong LD. Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res 2014; 59:189-202. [PMID: 25303559 DOI: 10.1002/mnfr.201400307] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 09/19/2014] [Accepted: 09/22/2014] [Indexed: 12/30/2022]
Affiliation(s)
- Jian-Mei Li
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Chen-Xu Ge
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Min-Xuan Xu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Wei Wang
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Rong Yu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Chen-Yu Fan
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
| | - Ling-Dong Kong
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing P. R. China
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AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet-induced nonalcoholic fatty liver disease. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2014; 1:14039. [PMID: 26015978 PMCID: PMC4362360 DOI: 10.1038/mtm.2014.39] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/26/2014] [Accepted: 07/18/2014] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease worldwide, and evidence suggests that it promotes insulin resistance and type 2 diabetes. Caloric restriction (CR) is the only available strategy for NAFLD treatment. The protein deacetylase Sirtuin1 (SIRT1), which is activated by CR, increases catabolic metabolism and decreases lipogenesis and inflammation, both involved in the development of NAFLD. Here we show that adeno-associated viral vectors of serotype 8 (AAV8)-mediated liver-specific Sirt1 gene transfer prevents the development of NAFLD induced by a high carbohydrate (HC) diet. Long-term hepatic SIRT1 overexpression led to upregulation of key hepatic genes involved in β-oxidation, prevented HC diet-induced lipid accumulation and reduced liver inflammation. AAV8-Sirt1-treated mice showed improved insulin sensitivity, increased oxidative capacity in skeletal muscle and reduced white adipose tissue inflammation. Moreover, HC feeding induced leptin resistance, which was also attenuated in AAV8-Sirt1-treated mice. Therefore, AAV-mediated gene transfer to overexpress SIRT1 specifically in the liver may represent a new gene therapy strategy to counteract NAFLD and related diseases such as type 2 diabetes.
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Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841:514-24. [DOI: 10.1016/j.bbalip.2014.01.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 12/13/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
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Betaine supplementation protects against high-fructose-induced renal injury in rats. J Nutr Biochem 2014; 25:353-62. [DOI: 10.1016/j.jnutbio.2013.11.010] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 11/18/2013] [Accepted: 11/18/2013] [Indexed: 01/26/2023]
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Rebollo A, Roglans N, Baena M, Padrosa A, Sánchez RM, Merlos M, Alegret M, Laguna JC. Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats. J Nutr Biochem 2014; 25:250-8. [DOI: 10.1016/j.jnutbio.2013.10.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 10/24/2013] [Accepted: 10/24/2013] [Indexed: 12/20/2022]
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Vasiljević A, Veličković N, Bursać B, Djordjevic A, Milutinović DV, Nestorović N, Matić G. Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats. J Nutr Biochem 2013; 24:1790-7. [DOI: 10.1016/j.jnutbio.2013.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 02/18/2013] [Accepted: 04/01/2013] [Indexed: 12/19/2022]
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Wang X, Zhang DM, Gu TT, Ding XQ, Fan CY, Zhu Q, Shi YW, Hong Y, Kong LD. Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway. Biochem Pharmacol 2013; 86:1791-804. [PMID: 24134913 DOI: 10.1016/j.bcp.2013.10.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 10/06/2013] [Accepted: 10/07/2013] [Indexed: 02/06/2023]
Abstract
SphK1/S1P signaling pathway is involved in the development of hepatic inflammation and injury. But its role in high fructose-induced NAFLD has not yet been reported. The aim of this study was to elucidate the crucial role of SphK1/S1P signaling pathway in high fructose-induced hepatic inflammation and lipid accumulation in rats. Moreover, the hepatoprotective effects of morin, a flavonoid with anti-inflammatory and anti-hyperlipedimic activities, on these hepatic changes in rats were investigated. High fructose-fed rats were orally treated with morin (30 and 60mg/kg) and pioglitazone (4mg/kg) for 8 weeks, respectively. Fructose feeding induced hyperlipidemia, and activated SphK1/S1P signaling pathway characterized by the elevation of SphK1 activity, S1P production as well as SphK1, S1PR1 and S1PR3 protein levels, which in turn caused NF-κB signaling activation to produce IL-1β, IL-6 and TNF-α and inflammation in the liver of rats. Subsequently, hepatic insulin and leptin signaling impairment and lipid metabolic disorder were observed in this animal model, resulting in liver lipid accumulation. Morin restored high fructose-induced the activation of hepatic SphK1/S1P signaling pathway in rats. Subsequently, the reduced NF-κB signaling activation by morin decreased inflammatory cytokine production, recovered insulin and leptin signaling impairment to reduce lipid accumulation and injury in the rat liver. These effects of morin were confirmed in Buffalo rat liver (BRL3A) cell model stimulated with 5mM fructose. Thus, the inhibition of hepatic SphK1/S1P signaling pathway may be a novel mechanism by which morin exerts hepatoprotection in high fructose-fed rats, possibly involving liver inflammation inhibition and lipid accumulation recovery.
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Affiliation(s)
- Xing Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China
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Yang J, Kang J, Guan Y. The mechanisms linking adiposopathy to type 2 diabetes. Front Med 2013; 7:433-44. [PMID: 24085616 DOI: 10.1007/s11684-013-0288-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 07/19/2013] [Indexed: 02/06/2023]
Abstract
Obesity is defined as excessive accumulation of body fat in proportion to body size. When obesity occurs, the functions of adipose tissue may be deregulated, which is termed as adiposopathy. Adiposopathy is an independent risk factor for many diseases, including diabetes and cardiovascular diseases. In overweight or obese subjects with adiposopathy, hyperlipidemia exerts lipotoxicity in pancreatic islet and liver and induces pancreatic β cell dysfunction and liver insulin resistance, which are the decisive factors causing type 2 diabetes. Moreover, adipokines have been shown to play important roles in the regulation of glucose homeostasis. When adiposopathy occurs, abnormal changes in the serum adipokine profile correlate with the development and progression of pancreatic β cell dysfunction and insulin resistance in peripheral tissue. The current paper briefly discusses the latest findings regarding the effects of adiposopathy-related lipotoxicity and cytokine toxicity on the development of type 2 diabetes.
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Affiliation(s)
- Jichun Yang
- Department of Physiology and Pathophysiology, Peking University Diabetes Center, Peking University Health Science Center, Beijing, 100191, China
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Abstract
BACKGROUND High carbohydrate intake has been linked to insulin resistance, obesity, and abnormal serum lipid profiles-conditions which favor gallstone formation. GOALS The aim of this study was to evaluate the effect of dietary carbohydrate intake on incident gallbladder disease, defined as biliary sludge and stones, during pregnancy. STUDY We prospectively studied 3070 pregnant women who underwent serial gallbladder ultrasound during pregnancy and at 4 to 6 weeks postpartum. All women had at least 2 study ultrasounds for comparison. A semiquantitative food frequency questionnaire was completed by subjects in the early third trimester. Multivariate logistic regression was performed to assess the risk of incident gallbladder disease across quartiles total and individual carbohydrate and individual carbohydrates (starch, sucrose, galactose, fructose, and lactose) intake. RESULTS The cumulative incidence of gallbladder disease was 10.2% by 4 to 6 weeks postpartum. The risk of incident gallbladder disease during pregnancy was significantly higher among women in the highest quartile of total carbohydrate intake versus those in the lowest quartile (odds ratio 2.09, 95% confidence interval 1.02-4.27). High intake of fructose was associated with increased risk even after additional adjustment for total carbohydrate intake (odds ratio 2.18, 95% confidence interval 1.23-3.86, comparing highest with lowest quartile). No association was found between the intake of starch, sucrose, lactose, or galactose and the risk of incident gallbladder disease. CONCLUSIONS High consumption of total carbohydrate and fructose may increase the risk of developing gallbladder disease during pregnancy. Dietary modification during pregnancy might reduce gallstone incidence during this time period.
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Mazzucco MB, Higa R, Capobianco E, Kurtz M, Jawerbaum A, White V. Saturated fat-rich diet increases fetal lipids and modulates LPL and leptin receptor expression in rat placentas. J Endocrinol 2013; 217:303-15. [PMID: 23482704 DOI: 10.1530/joe-13-0021] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Metabolic alterations in obese and overweight mothers impact the placenta and the fetus, leading to anomalies in fetal growth and lipid accretion. The primary aim of the study was to examine the effect of a saturated fat-rich diet (FD) on growth, lipid accretion, and lipases, leptin and leptin receptor (ObR) expression in the placenta and fetal liver. We also aimed to find a role for fetal leptin in the modulation of placental and fetal liver lipase and ObR expression. Six-week-old rats were fed with a standard rat chow (control) or a 25% FD for 7 weeks until mating and during pregnancy. Also, in a group of control rats, fetuses were injected with leptin on days 19, 20, and 21 of pregnancy. On day 21, we assessed lipidemia, insulinemia, and leptinemia in mothers and fetuses. In the placenta and fetal liver, lipid concentration was assessed by thin layer chromatography (TLC) and the gene expression of lipoprotein lipase (LPL), endothelial lipase, insulin receptor (Insr), leptin, and ObR by RT-PCR. The FD induced hypertriglyceridemia and hyperleptinemia (P<0.01) in mothers and fetuses, an increase in maternal (P<0.05) and fetal weight (P<0.01), overaccumulation of lipids in fetal liver (P<0.01), and enhanced leptin expression in the placenta and fetal liver (P<0.05). Placental expression of IR and LPL was increased (P<0.05), and ObR decreased (P<0.05) in the FD group. Fetal administration of leptin induced the placental and fetal liver downregulation of ObR (P<0.05) and upregulation of LPL expression (P<0.05). The FD led to increased fetal lipid levels, which may result from high maternal lipid availability and fetal leptin effects.
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Affiliation(s)
- M B Mazzucco
- Laboratory of Reproduction and Metabolism, School of Medicine, Center for Pharmacological and Botanical Studies, CEFyBO-CONICET, University of Buenos Aires, Paraguay 2155 17th floor CABA 1121, Buenos Aires, Argentina
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Chan SM, Sun RQ, Zeng XY, Choong ZH, Wang H, Watt MJ, Ye JM. Activation of PPARα ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress. Diabetes 2013; 62:2095-105. [PMID: 23349482 PMCID: PMC3661626 DOI: 10.2337/db12-1397] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and directly interfering with insulin signaling through the activation of the c-Jun N-terminal kinase (JNK) and IκB kinase (IKK) pathway. The current study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB) 100 mg/kg/day, a peroxisome proliferator-activated receptor α (PPARα) agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis, and the impaired hepatic insulin signaling (pAkt and pGSK3β). Of note, both the IRE1/XBP1 and PERK/eIF2α arms of unfolded protein response (UPR) signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS, and SCD1 and [3H]H2O incorporation into lipids), FB treatment markedly increased fatty acid oxidation (indicated by induction of ACOX1, p-ACC, β-HAD activity, and [14C]palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs), which is known to have an impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK, is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARα can ameliorate hepatic insulin resistance against increased ER stress.
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Affiliation(s)
- Stanley M.H. Chan
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Ruo-Qiong Sun
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Xiao-Yi Zeng
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Zi-Heng Choong
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Hao Wang
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Matthew J. Watt
- Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Melbourne, Victoria, Australia
| | - Ji-Ming Ye
- Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
- Corresponding author: Ji-Ming Ye,
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Rodríguez L, Panadero MI, Roglans N, Otero P, Alvarez-Millán JJ, Laguna JC, Bocos C. Fructose during pregnancy affects maternal and fetal leptin signaling. J Nutr Biochem 2013; 24:1709-16. [PMID: 23643523 DOI: 10.1016/j.jnutbio.2013.02.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 02/21/2013] [Accepted: 02/26/2013] [Indexed: 12/31/2022]
Abstract
Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. Fructose intake also causes features of metabolic syndrome in laboratory animals. Therefore, we have investigated whether fructose modifies lipidemia in pregnant rats and produces changes in their fetuses. Thus, fructose administration (10% wt/vol.) in the drinking water of rats throughout gestation leads to maternal hypertriglyceridemia. This change was not observed in glucose-fed rats, although both carbohydrates produced similar changes in liver triglycerides and in the expression of transcription factors and enzymes involved in lipogenesis. After fasting overnight, mothers fed with carbohydrates were found to be hyperleptinemic. However, after a bolus of glucose, leptinemia in fructose-fed mothers showed no response, whereas it increased in parallel in glucose-fed and control mothers. Fetuses from fructose-fed mothers showed hypotriglyceridemia and a higher hepatic triglyceride content than fetuses from control or glucose-fed mothers. A higher expression of genes related to lipogenesis and a lower expression of fatty acid catabolism genes were also found in fetuses from fructose-fed mothers. Moreover, although hyperleptinemic, these fetuses exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) protein, without a parallel increase in the serine phosphorylation of STAT-3 nor in the suppressor of cytokine signaling-3 protein levels whose expression is regulated by leptin through STAT-3 activation. Thus, fructose intake during gestation provoked a diminished maternal leptin response to fasting and refeeding and an impairment in the transduction of the leptin signal in the fetuses, which could be responsible for their hepatic steatosis.
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Affiliation(s)
- Lourdes Rodríguez
- Facultades de Farmacia y Medicina, Universidad San Pablo-CEU, Montepríncipe, Boadilla del Monte, Madrid, Spain
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Quercetin Preserves β -Cell Mass and Function in Fructose-Induced Hyperinsulinemia through Modulating Pancreatic Akt/FoxO1 Activation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:303902. [PMID: 23533474 PMCID: PMC3600179 DOI: 10.1155/2013/303902] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Revised: 01/26/2013] [Accepted: 01/26/2013] [Indexed: 12/20/2022]
Abstract
Fructose-induced hyperinsulinemia is associated with insulin compensative secretion and predicts the onset of type 2 diabetes. In this study, we investigated the preservation of dietary flavonoid quercetin on pancreatic β-cell mass and function in fructose-treated rats and INS-1 β-cells. Quercetin was confirmed to reduce serum insulin and leptin levels and blockade islet hyperplasia in fructose-fed rats. It also prevented fructose-induced β-cell proliferation and insulin hypersecretion in INS-1 β-cells. High fructose increased forkhead box protein O1 (FoxO1) expressions in vivo and in vitro, which were reversed by quercetin. Quercetin downregulated Akt and FoxO1 phosphorylation in fructose-fed rat islets and increased the nuclear FoxO1 levels in fructose-treated INS-1 β-cells. The elevated Akt phosphorylation in fructose-treated INS-1 β-cells was also restored by quercetin. Additionally, quercetin suppressed the expression of pancreatic and duodenal homeobox 1 (Pdx1) and insulin gene (Ins1 and Ins2) in vivo and in vitro. In fructose-treated INS-1 β-cells, quercetin elevated the reduced janus kinase 2/signal transducers and activators of transcription 3 (Jak2/Stat3) phosphorylation and suppressed the increased suppressor of cytokine signaling 3 (Socs3) expression. These results demonstrate that quercetin protects β-cell mass and function under high-fructose induction through improving leptin signaling and preserving pancreatic Akt/FoxO1 activation.
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