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Ding Z, Wang L, Sun J, Zheng L, Tang Y, Tang H. Hepatocellular carcinoma: pathogenesis, molecular mechanisms, and treatment advances. Front Oncol 2025; 15:1526206. [PMID: 40265012 PMCID: PMC12011620 DOI: 10.3389/fonc.2025.1526206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.
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Affiliation(s)
- Zhixian Ding
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lusheng Wang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Jiting Sun
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lijie Zheng
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Yu Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Heng Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
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Gursan A, de Graaf RA, Thomas MA, Prompers JJ, De Feyter HM. Deuterium MRS for In Vivo Measurement of Lipogenesis in the Liver. NMR IN BIOMEDICINE 2025; 38:e70014. [PMID: 39994887 DOI: 10.1002/nbm.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/24/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025]
Abstract
Hepatic de novo lipogenesis (DNL) plays a key role in the pathogenesis of several metabolic diseases that affect the liver. In humans, the detection of deuterium (2H) in triglycerides from very low density lipoprotein collected from blood after administration of deuterated water (D2O) is commonly used as an indirect estimate of hepatic DNL. Here, we tested in rats (1) the feasibility to detect 2H-labeling directly in liver lipids in vivo by using noninvasive 2H MRS and (2) to what extent these results correlated with the gold standard measurement of DNL in excised liver tissue. To increase hepatic DNL, half of the animals (n = 4) underwent a 7-week dietary intervention in which fructose was provided in drinking water. Deuterium MRS data were acquired from a single voxel placed in the liver. In vivo 2H MRS data showed 2H-labeling in the combined peak of methyl and methylene resonances after 1 week of administrati NBM_70014 on of 5% D2O as drinking water. DNL was calculated using 1H and 2H NMR data acquired from extracted lipids of excised liver tissue. The 2H lipid level measured in vivo correlated with the ex vivo estimates of hepatic DNL (r = 0.81, p = 0.016). These results demonstrate the feasibility of direct detection of deuterium labeling in liver lipids using localized 2H MRS in vivo and indicate the potential of this approach to measure hepatic DNL. These initial observations provide a basis for the method to be translated and to develop noninvasive, quantitative measurements of hepatic DNL in humans.
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Affiliation(s)
- Ayhan Gursan
- Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Robin A de Graaf
- Department of Radiology and Biomedical Imaging, Magnetic Resonance Research Center, Yale University, New Haven, Connecticut, USA
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA
| | - Monique A Thomas
- Department of Radiology and Biomedical Imaging, Magnetic Resonance Research Center, Yale University, New Haven, Connecticut, USA
| | - Jeanine J Prompers
- Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands
- Departments of Human Biology and Imaging, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Henk M De Feyter
- Department of Radiology and Biomedical Imaging, Magnetic Resonance Research Center, Yale University, New Haven, Connecticut, USA
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA
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Yadav P, Quadri K, Kadian R, Waziri A, Agrawal P, Alam MS. New approaches to the treatment of metabolic dysfunction-associated steatotic liver with natural products. ILIVER 2024; 3:100131. [DOI: 10.1016/j.iliver.2024.100131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Oshima T, Takaishi K, Nishihira M, Nguyen ST, Urakawa S, Ohno H, Fujita N. Detraining after short-term exercise induces hyperphagia and obesity with fatty liver and brown adipose tissue whitening in young male OLETF rats. Physiol Rep 2024; 12:e16055. [PMID: 38872474 PMCID: PMC11176740 DOI: 10.14814/phy2.16055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/04/2024] [Accepted: 05/04/2024] [Indexed: 06/15/2024] Open
Abstract
This study examined the effects of exercise and detraining at a young age on fat accumulation in various organs. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were assigned to either the non-exercise sedentary (OLETF Sed) or exercise groups. The exercise group was subdivided into two groups: exercise between 4 and 12 weeks of age (OLETF Ex) and exercise between 4 and 6 weeks of age followed by non-exercise between 6 and 12 weeks of age (OLETF DT). Body weight was significantly lower in the OLETF Ex group than in the OLETF Sed group at 12 weeks of age. Fat accumulation in the epididymal white adipose tissue, liver, and brown adipose tissue was suppressed in the OLETF Ex group. During the exercise period, body weight and food intake in the OLETF DT group were significantly lower than those in the OLETF Sed group. However, food intake was significantly higher in the OLETF DT group than in the OLETF Sed group after exercise cessation, resulting in extreme obesity with fatty liver and brown adipose tissue whitening. Detraining after early-onset exercise promotes hyperphagia, causing extreme obesity. Overeating should be avoided during detraining periods in cases of exercise cessation at a young age.
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Affiliation(s)
- Takaya Oshima
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kaho Takaishi
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Misuzu Nishihira
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Son Tien Nguyen
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Susumu Urakawa
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Haruya Ohno
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoto Fujita
- Department of Bio-Environmental Adaptation Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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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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Hendriks AD, Veltien A, Voogt IJ, Heerschap A, Scheenen TWJ, Prompers JJ. Glucose versus fructose metabolism in the liver measured with deuterium metabolic imaging. Front Physiol 2023; 14:1198578. [PMID: 37465695 PMCID: PMC10351417 DOI: 10.3389/fphys.2023.1198578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/20/2023] [Indexed: 07/20/2023] Open
Abstract
Chronic intake of high amounts of fructose has been linked to the development of metabolic disorders, which has been attributed to the almost complete clearance of fructose by the liver. However, direct measurement of hepatic fructose uptake is complicated by the fact that the portal vein is difficult to access. Here we present a new, non-invasive method to measure hepatic fructose uptake and metabolism with the use of deuterium metabolic imaging (DMI) upon administration of [6,6'-2H2]fructose. Using both [6,6'-2H2]glucose and [6,6'-2H2]fructose, we determined differences in the uptake and metabolism of glucose and fructose in the mouse liver with dynamic DMI. The deuterated compounds were administered either by fast intravenous (IV) bolus injection or by slow IV infusion. Directly after IV bolus injection of [6,6'-2H2]fructose, a more than two-fold higher initial uptake and subsequent 2.5-fold faster decay of fructose was observed in the mouse liver as compared to that of glucose after bolus injection of [6,6'-2H2]glucose. In contrast, after slow IV infusion of fructose, the 2H fructose/glucose signal maximum in liver spectra was lower compared to the 2H glucose signal maximum after slow infusion of glucose. With both bolus injection and slow infusion protocols, deuterium labeling of water was faster with fructose than with glucose. These observations are in line with a higher extraction and faster turnover of fructose in the liver, as compared with glucose. DMI with [6,6'-2H2]glucose and [6,6'-2H2]fructose could potentially contribute to a better understanding of healthy human liver metabolism and aberrations in metabolic diseases.
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Affiliation(s)
- Arjan D. Hendriks
- Center of Image Sciences, University Medical Center Utrecht, Utrecht, Netherlands
| | - Andor Veltien
- Department of Medical Imaging (Radiology), Radboud University Medical Center, Nijmegen, Netherlands
| | | | - Arend Heerschap
- Department of Medical Imaging (Radiology), Radboud University Medical Center, Nijmegen, Netherlands
| | - Tom W. J. Scheenen
- Department of Medical Imaging (Radiology), Radboud University Medical Center, Nijmegen, Netherlands
| | - Jeanine J. Prompers
- Center of Image Sciences, University Medical Center Utrecht, Utrecht, Netherlands
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Effects of Different Vegetable Oils on the Nonalcoholic Fatty Liver Disease in C57/BL Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2023; 2023:4197955. [PMID: 36691598 PMCID: PMC9867581 DOI: 10.1155/2023/4197955] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 01/15/2023]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, affecting 22-28% of the adult population and more than 50% of obese people all over the world. Modulation of the fatty acids in diet as a means of prevention against nonalcoholic fatty liver disease in animal models (NAFLD) remains unclear. The treatment of NAFLD has not been described in specific guidelines so far. Thus, the justification for the study is to check modifications in macronutrients composition, fatty acids, in particular, play a significant role in the treatment of NAFLD regardless of weight loss. Aim To investigate different vegetable oils in prevention and progression of NAFLD in animal models. Methods For the experiment were used fifty C57BL/6J mice male fed with high fat and fructose diet (HFD) to induce the NAFLD status and they received different commercial vegetable oils for 16 weeks to prevent steatosis. Liver steatosis and oxidative stress parameters were analyzed using biochemical and histological methods. Fatty acids profile in the oils and in the liver samples was obtained. Results The high fat and fructose diet led to obesity and the vegetable oils offered were effective in maintaining body weight similar to the control group. At the end of the experiment (16 weeks), the HFHFr group had a greater body weight compared to control and treated groups (HFHFr: 44.20 ± 2.34 g/animal vs. control: 34.80 ± 3.45 g/animal; p < 0.001; HFHFr/OL: 35.40 ± 4.19 g/animal; HFHFr/C: 36.10 ± 3.92 g/animal; HFHFr/S: 36.25 ± 5.70 g/animal; p < 0.01). Furthermore, the HFD diet has caused an increase in total liver fat compared to control (p < 0.01). Among the treated groups, the animals receiving canola oil showed a reduction of hepatic and retroperitoneal fat (p < 0.05). These biochemical levels were positively correlated with the hepatic histology findings. Hepatic levels of omega-3 decreased in the olive oil and high fat diet groups compared to the control group, whereas these levels increased in the groups receiving canola and soybean oil compared to control and the high fat groups. Conclusion In conclusion, the commercial vegetable oils either contributed to the prevention or reduction of induced nonalcoholic fatty liver with high fat and fructose diet, especially canola oil.
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Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment. Int J Mol Sci 2022; 23:ijms232415489. [PMID: 36555127 PMCID: PMC9779435 DOI: 10.3390/ijms232415489] [Citation(s) in RCA: 161] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. A range of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the pathogenesis of NAFLD and some natural products that have been shown to have therapeutic effects on NAFLD. Our work shows that natural products can be a potential therapeutic option for NAFLD.
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Mandour MO, El-Hassan M, Elkomi RM, Oben JA. Non-alcoholic fatty liver disease: Is surgery the best current option and can novel endoscopy play a role in the future? World J Hepatol 2022; 14:1704-1717. [PMID: 36185721 PMCID: PMC9521460 DOI: 10.4254/wjh.v14.i9.1704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/06/2023] Open
Abstract
Over the last decade, non-alcoholic fatty liver disease (NAFLD) has overtaken alcohol as the leading cause of cirrhosis in the Western world. There remains to be a licensed pharmacological treatment for NAFLD. Weight loss is advised for all patients with NAFLD. Many patients however, struggle to lose the recommended weight with lifestyle modification alone. Many drugs have either failed to show significant improvement of steatosis or are poorly tolerated. Bariatric surgery has been shown to reduce liver steatosis and regress liver fibrosis. The pathophysiology is not fully understood, however recent evidence has pointed towards changes in the gut microbiome following surgery. Novel endoscopic treatment options provide a minimally invasive alternative for weight loss. Randomised controlled trials are now required for further clarification.
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Affiliation(s)
- Mandour Omer Mandour
- Department of Gastroenterology and Hepatology, Guys & St Thomas Hospital, London, SE1 7EH, United Kingdom
| | - Mohammed El-Hassan
- Department of Gastroenterology and Hepatology, Guys & St Thomas Hospital, London, SE1 7EH, United Kingdom
| | - Rawan M Elkomi
- Department of Gastroenterology and Hepatology, Guys & St Thomas Hospital, London, SE1 7EH, United Kingdom
| | - Jude A Oben
- Department of Gastroenterology and Hepatology, Guys & St Thomas Hospital, London, SE1 7EH, United Kingdom
- King’s College London, School of Life Course Sciences, Faculty of Life Sciences and Medicine, London SE1 7EH, United Kingdom
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Xie J, Shi S, Liu Y, Wang S, Rajput SA, Song T. Fructose metabolism and its role in pig production: A mini-review. Front Nutr 2022; 9:922051. [PMID: 35967778 PMCID: PMC9373593 DOI: 10.3389/fnut.2022.922051] [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: 04/17/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022] Open
Abstract
Epidemiological studies have shown that excessive intake of fructose is largely responsible for the increasing incidence of non-alcoholic fatty liver, obesity, and diabetes. However, depending on the amount of fructose consumption from diet, the metabolic role of fructose is controversial. Recently, there have been increasing studies reporting that diets low in fructose expand the surface area of the gut and increase nutrient absorption in mouse model, which is widely used in fructose-related studies. However, excessive fructose consumption spills over from the small intestine into the liver for steatosis and increases the risk of colon cancer. Therefore, suitable animal models may be needed to study fructose-induced metabolic changes. Along with its use in global meat production, pig is well-known as a biomedical model with an advantage over murine and other animal models as it has similar nutrition and metabolism to human in anatomical and physiological aspects. Here, we review the characteristics and metabolism of fructose and summarize observations of fructose in pig reproduction, growth, and development as well as acting as a human biomedical model. This review highlights fructose metabolism from the intestine to the blood cycle and presents the critical role of fructose in pig, which could provide new strategies for curbing human metabolic diseases and promoting pig production.
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Affiliation(s)
- Jiahao Xie
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Shiyi Shi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yucheng Liu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Shaoshuai Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Shahid Ali Rajput
- Faculty of Veterinary and Animal Sciences, Muhammad Nawaz Shareef University of Agriculture Multan, Multan, Pakistan
| | - Tongxing Song
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
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Portincasa P, Celano G, Serale N, Vitellio P, Calabrese FM, Chira A, David L, Dumitrascu DL, De Angelis M. Clinical and Metabolomic Effects of Lactiplantibacillus plantarum and Pediococcus acidilactici in Fructose Intolerant Patients. Nutrients 2022; 14:2488. [PMID: 35745219 PMCID: PMC9231202 DOI: 10.3390/nu14122488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/12/2022] [Accepted: 06/13/2022] [Indexed: 12/10/2022] Open
Abstract
Fructose intolerance (FI) is a widespread non-genetic condition in which the incomplete absorption of fructose leads to gastro-intestinal disorders. The crucial role of microbial dysbiosis on the onset of these intolerance symptoms together with their persistence under free fructose diets are driving the scientific community towards the use of probiotics as a novel therapeutic approach. In this study, we evaluated the prevalence of FI in a cohort composed of Romanian adults with Functional Grastrointestinal Disorders (FGIDs) and the effectiveness of treatment based on the probiotic formulation EQBIOTA® (Lactiplantibacillus plantarum CECT 7484 and 7485 and Pediococcus acidilactici CECT 7483). We evaluated the impact of a 30-day treatment both on FI subjects and healthy volunteers. The gastrointestinal symptoms and fecal volatile metabolome were evaluated. A statistically significant improvement of symptoms (i.e., bloating, and abdominal pain) was reported in FI patient after treatment. On the other hand, at the baseline, the content of volatile metabolites was heterogeneously distributed between the two study arms, whereas the treatment led differences to decrease. From our analysis, how some metabolomics compounds were correlated with the improvement and worsening of clinical symptoms clearly emerged. Preliminary observations suggested how the improvement of gastrointestinal symptoms could be induced by the increase of anti-inflammatory and protective substrates. A deeper investigation in a larger patient cohort subjected to a prolonged treatment would allow a more comprehensive evaluation of the probiotic treatment effects.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy
| | - Giuseppe Celano
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università Degli Studi di Bari Aldo Moro, 70126 Bari, Italy; (G.C.); (N.S.); (P.V.); (F.M.C.)
| | - Nadia Serale
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università Degli Studi di Bari Aldo Moro, 70126 Bari, Italy; (G.C.); (N.S.); (P.V.); (F.M.C.)
| | - Paola Vitellio
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università Degli Studi di Bari Aldo Moro, 70126 Bari, Italy; (G.C.); (N.S.); (P.V.); (F.M.C.)
| | - Francesco Maria Calabrese
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università Degli Studi di Bari Aldo Moro, 70126 Bari, Italy; (G.C.); (N.S.); (P.V.); (F.M.C.)
| | - Alexandra Chira
- 2nd Department of Internal Medicine, ‘Iuliu Hatieganu’ University of Medicine and Farmacy, 400012 Cluj-Napoca, Romania; (A.C.); (L.D.)
| | - Liliana David
- 2nd Department of Internal Medicine, ‘Iuliu Hatieganu’ University of Medicine and Farmacy, 400012 Cluj-Napoca, Romania; (A.C.); (L.D.)
| | - Dan L. Dumitrascu
- 2nd Department of Internal Medicine, ‘Iuliu Hatieganu’ University of Medicine and Farmacy, 400012 Cluj-Napoca, Romania; (A.C.); (L.D.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università Degli Studi di Bari Aldo Moro, 70126 Bari, Italy; (G.C.); (N.S.); (P.V.); (F.M.C.)
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Réggami Y, Benkhaled A, Boudjelal A, Berredjem H, Amamra A, Benyettou H, Larabi N, Senator A, Siracusa L, Ruberto G. Artemisia herba-alba aqueous extract improves insulin sensitivity and hepatic steatosis in rodent model of fructose-induced metabolic syndrome. Arch Physiol Biochem 2021; 127:541-550. [PMID: 31464524 DOI: 10.1080/13813455.2019.1659825] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONTEXT Fructose consumption is associated with the development of obesity and metabolic syndrome (MetS) in human and animal models. OBJECTIVE This study investigates the ability of an aqueous extract of Artemisia herba-alba Asso (AH) to ameliorate fructose-induced MetS in Male Wistar rats. METHODS AH extract at doses of 100, 200 and 400 mg/kg b.w./day was administered for six weeks to MetS animals. RESULTS Liquid fructose (10% w/v) intake did not vary total animal body weight, whereas, it produced moderate hyperglycemia associated with metabolic and histological alterations. Treating MetS rats with AH extract improved insulin sensitivity, alleviated atherogenic dyslipidaemia and decreased lipid deposition in their hepatic tissues. Additionally, AH extract was found to raise GSH level and antioxidant enzymes (GPx, GST and CAT) activities in rat livers homogenates. CONCLUSION The results here reported demonstrated, for the first time, that A. herba-alba have therapeutic proprieties against fructose-induced MetS in rodent model.
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Affiliation(s)
- Yassine Réggami
- Department of Microbiology and Biochemistry, Faculty of Sciences, Mohamed Boudiaf-M'sila University, M'sila, Algeria
- Laboratory of Biochemistry and Applied Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Abderrahim Benkhaled
- Department of Microbiology and Biochemistry, Faculty of Sciences, Mohamed Boudiaf-M'sila University, M'sila, Algeria
| | - Amel Boudjelal
- Department of Microbiology and Biochemistry, Faculty of Sciences, Mohamed Boudiaf-M'sila University, M'sila, Algeria
| | - Hajira Berredjem
- Laboratory of Biochemistry and Applied Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Amani Amamra
- Laboratory of Biochemistry and Applied Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Halima Benyettou
- Department of Microbiology and Biochemistry, Faculty of Sciences, Mohamed Boudiaf-M'sila University, M'sila, Algeria
| | - Nadia Larabi
- Department of Microbiology and Biochemistry, Faculty of Sciences, Mohamed Boudiaf-M'sila University, M'sila, Algeria
| | - Abderrahmane Senator
- Laboratory of Applied Biochemistry, Faculty of Natural and Life Sciences, Ferhat Abbas-Setif University, Setif, Algeria
| | - Laura Siracusa
- Istituto di Chimica Biomolecolare del Consiglio Nazionale delle Ricerche (ICB-CNR), Catania, Italy
| | - Giuseppe Ruberto
- Istituto di Chimica Biomolecolare del Consiglio Nazionale delle Ricerche (ICB-CNR), Catania, Italy
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Federico A, Rosato V, Masarone M, Torre P, Dallio M, Romeo M, Persico M. The Role of Fructose in Non-Alcoholic Steatohepatitis: Old Relationship and New Insights. Nutrients 2021; 13:1314. [PMID: 33923525 PMCID: PMC8074203 DOI: 10.3390/nu13041314] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/12/2021] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the result of hepatic fat overload not due to alcohol consumption and potentially evolving to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fructose is a naturally occurring simple sugar widely used in food industry linked to glucose to form sucrose, largely contained in hypercaloric food and beverages. An increasing amount of evidence in scientific literature highlighted a detrimental effect of dietary fructose consumption on metabolic disorders such as insulin resistance, obesity, hepatic steatosis, and NAFLD-related fibrosis as well. An excessive fructose consumption has been associated with NAFLD development and progression to more clinically severe phenotypes by exerting various toxic effects, including increased fatty acid production, oxidative stress, and worsening insulin resistance. Furthermore, some studies in this context demonstrated even a crucial role in liver cancer progression. Despite this compelling evidence, the molecular mechanisms by which fructose elicits those effects on liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. This review aimed to summarize the current understanding of fructose metabolism on NAFLD pathogenesis and progression.
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Affiliation(s)
- Alessandro Federico
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Valerio Rosato
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
| | - Pietro Torre
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
| | - Marcello Dallio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Mario Romeo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Marcello Persico
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
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Mehta R, Sonavane M, Migaud ME, Gassman NR. Exogenous exposure to dihydroxyacetone mimics high fructose induced oxidative stress and mitochondrial dysfunction. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2021; 62:185-202. [PMID: 33496975 PMCID: PMC7954877 DOI: 10.1002/em.22425] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 05/09/2023]
Abstract
Dihydroxyacetone (DHA) is a three-carbon sugar that is the active ingredient in sunless tanning products and a by-product of electronic cigarette (e-cigarette) combustion. Increased use of sunless tanning products and e-cigarettes has elevated exposures to DHA through inhalation and absorption. Studies have confirmed that DHA is rapidly absorbed into cells and can enter into metabolic pathways following phosphorylation to dihydroxyacetone phosphate (DHAP), a product of fructose metabolism. Recent reports have suggested metabolic imbalance and cellular stress results from DHA exposures. However, the impact of elevated exposure to DHA on human health is currently under-investigated. We propose that exogenous exposures to DHA increase DHAP levels in cells and mimic fructose exposures to produce oxidative stress, mitochondrial dysfunction, and gene and protein expression changes. Here, we review cell line and animal model exposures to fructose to highlight similarities in the effects produced by exogenous exposures to DHA. Given the long-term health consequences of fructose exposure, this review emphasizes the pressing need to further examine DHA exposures from sunless tanning products and e-cigarettes.
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Affiliation(s)
- Raj Mehta
- Department of Physiology and Cell Biology, University of South Alabama, College of Medicine, Mobile, AL USA
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL USA
| | - Manoj Sonavane
- Department of Physiology and Cell Biology, University of South Alabama, College of Medicine, Mobile, AL USA
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL USA
| | - Marie E. Migaud
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL USA
- Department of Pharmacology, University of South Alabama, College of Medicine, Mobile, AL USA
| | - Natalie R. Gassman
- Department of Physiology and Cell Biology, University of South Alabama, College of Medicine, Mobile, AL USA
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL USA
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15
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Roeb E, Weiskirchen R. Fructose and Non-Alcoholic Steatohepatitis. Front Pharmacol 2021; 12:634344. [PMID: 33628193 PMCID: PMC7898239 DOI: 10.3389/fphar.2021.634344] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The excessive consumption of free sugars is mainly responsible for the high prevalence of obesity and metabolic syndrome in industrialized countries. More and more studies indicate that fructose is involved in the pathophysiology and also in the degree of disease of non-alcoholic fatty liver disease (NAFLD). In epidemiologic studies, energy-adjusted higher fructose consumption correlates with NAFLD in overweight adults. In addition to glucose, fructose, as an equivalent component of conventional household sugar, appears to have negative metabolic effects in particular due to its exclusive hepatic metabolism. Liver-related mortality is strictly associated with the degree of fibrosis, whereas the most common cause of death in patients suffering from NAFLD and non-alcoholic steatohepatitis (NASH) are still cardiovascular diseases. In this review article, we have summarized the current state of knowledge regarding a relationship between fructose consumption, liver fibrosis and life expectancy in NASH. Method: Selective literature search in PubMed using the keywords 'non-alcoholic fatty liver', 'fructose', and 'fibrosis' was conducted. Results: The rate of overweight and obesity is significantly higher in both, adult and pediatric NASH patients. The consumption of free sugars is currently three times the maximum recommended amount of 10% of the energy intake. The current literature shows weight gain, negative effects on fat and carbohydrate metabolism and NASH with hypercaloric intake of fructose. Conclusions: Excessive fructose consumption is associated with negative health consequences. Whether this is due to an excess of energy or the particular metabolism of fructose remains open with the current study situation. The urgently needed reduction in sugar consumption could be achieved through a combination of binding nutritional policy measures including taxation of sugary soft drinks. Previous studies suggest that diet-related fructose intake exceeding the amount contained in vegetables and fruits lead to an increase of hepatic lipogenesis. Thus, further studies to clarify the protective contribution of low-fructose intake to positively influence NAFLD in industrial population are urgently required.
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Affiliation(s)
- Elke Roeb
- Department of Gastroenterology, Justus Liebig University Giessen and University Hospital Giessen, Giessen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
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16
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The Postnatal Offspring of Finasteride-Treated Male Rats Shows Hyperglycaemia, Elevated Hepatic Glycogen Storage and Altered GLUT2, IR, and AR Expression in the Liver. Int J Mol Sci 2021; 22:ijms22031242. [PMID: 33513940 PMCID: PMC7865973 DOI: 10.3390/ijms22031242] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Background: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T–DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. Methods: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman’s rank correlation coefficients. Results: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A). Conclusions: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.
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Jakhmola-Mani R, Islam A, Katare DP. Liver-Brain Axis in Sporadic Alzheimer's Disease: Role of Ten Signature Genes in a Mouse model. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2020; 20:871-885. [PMID: 33297922 DOI: 10.2174/1871527319666201209111006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 08/23/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022]
Abstract
AIM Poor nutritional effect of junk food induces injurious adversities to the liver and brain but still most of the developing nations survives on these diets to compensate for fast-paced lifestyle. Aim of the study is to infer the proteinconnections behind liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. BACKGROUND Chronic consumption of fructose and fat rich food works as a toxin in body and have the ability to cause negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects in liver as well brain. This work provides insights into liver-brain axis and explains how liver is involved in brain related disorders. OBJECTIVE In this study transcriptomic data relating to chronic eating of junk-food was analyzed and simultaneous damage that happens in liver and brain was assessed at molecular level. METHOD Transcriptomic study was taken from GEO database and analysed to find out the genes dysregulated in both liver and brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between liver and brain. This connection between both was called as Liver-Brain axis. RESULT The results obtained from our study indicates the role of TUBB5-HYOU1-SDF2L1-DECR1-CDH1-EGFR-SKP2- SOD1-IRAK1-FOXO1 gene signature towards the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. CONCLUSION We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer's disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (nonalcoholic fatty liver disease) and sAD (sporadic Alzheimer's disease) owing to liver-brain axis.
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Affiliation(s)
- Ruchi Jakhmola-Mani
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
| | - Anam Islam
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
| | - Deepshikha Pande Katare
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
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18
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Triose Kinase Controls the Lipogenic Potential of Fructose and Dietary Tolerance. Cell Metab 2020; 32:605-618.e7. [PMID: 32818435 DOI: 10.1016/j.cmet.2020.07.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 04/16/2020] [Accepted: 07/28/2020] [Indexed: 01/01/2023]
Abstract
The surge in fructose consumption is a major factor behind the rapid rise of nonalcoholic fatty liver disease in modern society. Through flux and genetic analyses, we demonstrate that fructose is catabolized at a much higher rate than glucose, and triose kinase (TK) couples fructolysis with lipogenesis metabolically and transcriptionally. In the absence of TK, fructose oxidation is accelerated through the activation of aldehyde dehydrogenase (ALDH) and serine biosynthesis, accompanied by increased oxidative stress and fructose aversion. TK is also required by the endogenous fructolysis pathway to drive lipogenesis and hepatic triglyceride accumulation under high-fat diet and leptin-deficient conditions. Intriguingly, a nonsynonymous TK allele (rs2260655_A) segregated during human migration out of Africa behaves as TK null for its inability to rescue fructose toxicity and increase hepatic triglyceride accumulation. Therefore, we posit TK as a metabolic switch controlling the lipogenic potential of fructose and its dietary tolerance.
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19
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Effects on weaned male Wistar rats after 104, 197, and 288 days of chronic consumption of nutritive and non-nutritive additives in water. Journal of Food Science and Technology 2020; 58:2349-2359. [PMID: 33967331 DOI: 10.1007/s13197-020-04746-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 08/13/2020] [Accepted: 08/18/2020] [Indexed: 12/17/2022]
Abstract
Abstract It has been suggested that the consumption of artificial sweeteners is related to greater body mass gain and diverse metabolic alterations. In this study, the effect of chronic consumption of nutritive sweeteners (fructose 7% and sucrose 10%) and non-nutritive or low-calorie sweeteners (acesulfame 0.015%, aspartame 0.3%, aspartame:acesulfame mixture 0.04%, saccharin 0.3%, and sucralose 0.19%), in drinking water, as well as a control group with no sweeteners, was evaluated. Body mass gain and glucose, insulin, triglycerides, and total cholesterol levels in blood were the parameters considered. For this purpose, 120 weaned male Wistar rats of the HsdHan:WIST line were used, 15 per group in first stage, then 10 and 5 per group for 2nd and 3rd stages, respectively. Body mass gain, food intake, and beverage consumption were daily quantified. After 104, 197, and 288 days of experimentation the concentrations of glucose, triglycerides, cholesterol, and insulin were determined. Only in the first stage there were significant differences in the body mass gain. In the three stages there were significant differences in the patterns of beverage intake and food consumption. The trend was the same in all 3 stages: rats drank more in the groups of drinks sweetened with nutritive sweeteners and ate more in the groups that drank non-nutritive artificial sweeteners. Regarding the biochemical profile, no sweetener either nutritive or non-nutritive caused that the serum levels of glucose, triglycerides, and cholesterol were at pathological levels. It is concluded that the sweeteners by themselves can modify certain biochemical parameters but not at a pathological level. Furthermore, by themselves they are not capable of triggering excess of body mass or obesity in the early and medium stages of life when consumed together with a balanced diet. Graphic abstract
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20
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Differential Effects of Chronic Ingestion of Refined Sugars versus Natural Sweeteners on Insulin Resistance and Hepatic Steatosis in a Rat Model of Diet-Induced Obesity. Nutrients 2020; 12:nu12082292. [PMID: 32751772 PMCID: PMC7469035 DOI: 10.3390/nu12082292] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 01/07/2023] Open
Abstract
While the detrimental effect of refined sugars on health has been the subject of many investigations, little is known about the long-term impact of natural sweeteners on metabolic disorders. In this study we compared the metabolic responses to chronic ingestion of refined sugars compared to various natural sweeteners in diet-induced obese rats. Wistar rats were fed a high-fat high-sucrose diet (HFHS) for 8 weeks and daily gavaged with a solution containing 1 g of total carbohydrates from refined sugar (sucrose or fructose) or six different natural sugar sources, followed by assessment of glucose homeostasis, hepatic lipid accumulation, and inflammation. While glucose tolerance was similar following treatments with refined and natural sugars, lowered glucose-induced hyperinsulinemia was observed with fructose. Consumption of fructose and all-natural sweeteners but not corn syrup were associated with lower insulin resistance as revealed by reduced fasting insulin and homeostatic model assessment of insulin resistance (HOMA-IR) compared to sucrose treatment of HFHS-fed rats. All-natural sweeteners and fructose induced similar liver lipid accumulation as sucrose. Nevertheless, maple syrup, molasses, agave syrup, and corn syrup as well as fructose further reduced hepatic IL-1β levels compared to sucrose treatment. We conclude that natural sweeteners and especially maple syrup, molasses, and agave syrup attenuate the development of insulin resistance and hepatic inflammation compared to sucrose in diet-induced obese rats, suggesting that consumption of those natural sweeteners is a less harmful alternative to sucrose in the context of obesity.
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Kumar V, Sachan R, Rahman M, Sharma K, Al-Abbasi FA, Anwar F. Prunus amygdalus extract exert antidiabetic effect via inhibition of DPP-IV: in-silico and in-vivo approaches. J Biomol Struct Dyn 2020; 39:4160-4174. [PMID: 32602806 DOI: 10.1080/07391102.2020.1775124] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Prunus amygdalus (PA) is a popular invasive seed utilized in the management of diabetes in Jammu and Kashmir, India. The objective of the current study was to scrutinize the antidiabetic effect of Prunus amygdalus (PA) against Streptozotocin (STZ) induced diabetic rats and explore the possible mechanism of action at cellular and sub-cellular levels. Box Benkan Design (BBD) was performed to determine the effect of PA powder to methanol, extraction time and extraction temperature on DPPH and ABTS free radical scavenging activity of decoction. In-silico study was performed on GLUT1 (5EQG) and dipeptidyl peptidase IV (DPPIV) (2G63) protein. Type II diabetes mellitus was initiated by single intra-peritoneal injection of STZ. The Blood Glucose Level (BGL) and body weight were estimated at regular interval of time. The different biochemical parameters such as hepatic, antioxidant, and lipid parameters were estimated. At end of the study, pancreas was used for histopathological observation. The variation in DPPH antiradical scavenging activity 40.0-90.0% and ABTS antiradical scavenging activity 34-82%, were estimated respectively. STZ induced DM rats showed increased BGL at end of the experimental study. PA treatment significantly (p < 0.001) down-regulated the BGL level. PA significantly (p < 0.001) altered the biochemical, hepatic and antioxidant parameters in a dose-dependent manner. Histopathological examination demonstrated the constructive mass of β-cells in pancreas. Overall, the current study indicates that the PA treatment down-regulated the hyperglycemic, oxidative stress and hyperlipidaemia in diabetic rats, due to inhibition of enzymes or amelioration of oxidative stress. [Formula: see text] Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, India
| | - Richa Sachan
- School of Pharmacy, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon, Korea
| | - Mahfoozur Rahman
- Faculty of Health Sciences, Department of Pharmaceutical Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, India
| | - Kalicharan Sharma
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, SPER, Jamia Hamdard, New Delhi, India
| | - Fahad A Al-Abbasi
- Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Firoz Anwar
- Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
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22
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Ibrahim KG, Chivandi E, Nkomozepi P, Matumba MG, Mukwevho E, Erlwanger KH. The long-term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high-fructose-fed adolescent rats. Physiol Rep 2020; 7:e14032. [PMID: 30912307 PMCID: PMC6692695 DOI: 10.14814/phy2.14032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 02/27/2019] [Accepted: 03/01/2019] [Indexed: 12/15/2022] Open
Abstract
There is an increased prevalence of nonalcoholic steatohepatitis (NASH) in adolescents. The suckling period is developmentally plastic, affecting later health outcomes. We investigated whether neonatal administration of curcumin would provide protection against the development of NASH later in adolescence in rats fed a high-fructose diet. From postnatal day (PN) 6 to PN 21, the pups (N = 128) were allocated to four groups and orally gavaged daily with either 0.5% dimethyl sulfoxide solution (vehicle control), curcumin (500 mg·kg-1 ), fructose (20%, w/v) or curcumin and fructose combined. All the pups were weaned and half the rats in each group had tap water, whereas the other received fructose (20%) as their drinking fluid ad libitum for 6 weeks. The rats' liver NASH scores, lipid content, and RNA gene expression ratios of AMPKα and TNFα were determined. Hepatic lipid content was similar across the treatment groups in the males (P > 0.05, ANOVA). In the females, the hepatic lipid content in the treatment groups ranged from 2.7 to 4.3%. The livers of male and female rats that had fructose either as neonates and/or postweaning had significantly marked inflammation (P = 0.0112, Kruskal-Wallis) and fibrosis (P < 0.0001, ANOVA) which were attenuated by curcumin. The hepatic gene expression ratios for AMPKα in both sexes were significantly downregulated (P < 0.0001, ANOVA), whereas the expression ratios of TNFα were significantly upregulated (P < 0.0001) in rats fed a high-fructose diet pre and/or postweaning compared to the other groups. Neonatal curcumin administration is a potential natural pharmacological candidate for the prevention of NASH.
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Affiliation(s)
- Kasimu G Ibrahim
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.,Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Eliton Chivandi
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Pilani Nkomozepi
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Doornfontein, Johannesburg, South Africa
| | - Mashudu G Matumba
- Department of Biochemistry, Faculty of Natural Sciences & Agriculture, North-West University, Mmabatho, Mafikeng, South Africa
| | - Emmanuel Mukwevho
- Department of Biochemistry, Faculty of Natural Sciences & Agriculture, North-West University, Mmabatho, Mafikeng, South Africa
| | - Kennedy H Erlwanger
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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23
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Cha SH, Hwang Y, Heo SJ, Jun HS. Indole-4-carboxaldehyde Isolated from Seaweed, Sargassum thunbergii, Attenuates Methylglyoxal-Induced Hepatic Inflammation. Mar Drugs 2019; 17:E486. [PMID: 31438528 PMCID: PMC6780312 DOI: 10.3390/md17090486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/19/2019] [Accepted: 08/16/2019] [Indexed: 12/16/2022] Open
Abstract
Glucose degradation is aberrantly increased in hyperglycemia, which causes various harmful effects on the liver. Glyoxalase-1 (Glo-1) is a ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MGO), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end-products, AGEs) and inflammation. Here, we investigated the anti-inflammatory effect of indole-4-carboxaldehyde (ST-I4C), which was isolated from the edible seaweed Sargassum thunbergii, on MGO-induced inflammation in HepG2 cells, a human hepatocyte cell line. ST-I4C attenuated the MGO-induced expression of inflammatory-related genes, such as tumor necrosis factor (TNF)-α and IFN-γ by activating nuclear factor-kappa B (NF-κB) without toxicity in HepG2 cells. In addition, ST-I4C reduced the MGO-induced AGE formation and the expression of the receptor for AGE (RAGE). Interestingly, both the mRNA and protein expression levels of Glo-1 increased following ST-I4C treatment, and the decrease in Glo-1 mRNA expression caused by MGO exposure was rescued by ST-I4C pretreatment. These results suggest that ST-I4C shows anti-inflammatory activity against MGO-induced inflammation in human hepatocytes by preventing an increase in the pro-inflammatory gene expression and AGE formation. Therefore, it represents a potential therapeutic agent for the prevention of hepatic steatosis.
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Affiliation(s)
- Seon-Heui Cha
- Department of Marine Biomedical Sciences, Hanseo University, Chungcheongnam-do 31962, Korea
| | - Yongha Hwang
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
- College of Pharmacy, Gachon University, Incheon 21999, Korea
| | - Soo-Jin Heo
- Jeju International Marine Science Center for Research & Education, Korea Institute of Ocean Science & Technology (KIOST), Jeju 63349, Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea.
- College of Pharmacy, Gachon University, Incheon 21999, Korea.
- Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon 21999, Korea.
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Khalilnezhad A, Taskiran D. The investigation of protective effects of glucagon-like peptide-1 (GLP-1) analogue exenatide against glucose and fructose-induced neurotoxicity. Int J Neurosci 2019; 129:481-491. [PMID: 30422728 DOI: 10.1080/00207454.2018.1543671] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by hyperglycemia due to insufficiency of insulin and/or insulin resistance. Clinical studies have revealed a higher risk of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease in diabetic patients. Recently, glucagon-like peptide-1 (GLP-1) is an attractive potential treatment modality for various neurodegenerative diseases. In our study, we aimed to investigate whether exenatide, a GLP-1 analogue, has neuroprotective effects against glucose and fructose-induced toxicity in human SH-SY5Y neuroblastoma cell line. Neurotoxicity was induced by incubating SH-SY5Y cells with different doses (25-100 mM) of glucose and fructose for 24, 48 and 72 hours. Following determination of the significant toxic doses of glucose and fructose, the cells were treated with various doses of exenatide (10-250 nM) in the presence or absence of glucose and fructose. Neurotoxicity was evaluated by MTT assay and Hoechst 33258 staining. Caspase-3 activity and the levels of advanced glycation end products (AGEs) were determined in the cytosolic fractions of treated cells. Our results demonstrated that both glucose and fructose treatments decreased cell viability in neuronal cells dose and time-dependently. Glucose and fructose-treated groups showed increased numbers of apoptotic cells, caspase-3 activity and AGEs levels. Treatment of the cells with exenatide significantly prevented cell death. The most prominent effect was observed at 100 nM exenatide-treated cultures. Our results suggest that high doses of glucose and fructose may lead to neurotoxicity, and exenatide may have protective effects against neuronal damage through its anti-apoptotic feature.
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Affiliation(s)
- Asghar Khalilnezhad
- a Department of Physiology, Ege University School of Medicine , Izmir , Turkey
| | - Dilek Taskiran
- a Department of Physiology, Ege University School of Medicine , Izmir , Turkey
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Yang L, Li Z, Song Y, Liu Y, Zhao H, Liu Y, Zhang T, Yuan Y, Cai X, Wang S, Wang P, Gao S, Li L, Li Y, Yu C. Study on urine metabolic profiling and pathogenesis of hyperlipidemia. Clin Chim Acta 2019; 495:365-373. [PMID: 31059703 DOI: 10.1016/j.cca.2019.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 04/14/2019] [Accepted: 05/02/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND As a recognized risk factor for cardiovascular disease (CVD), hyperlipidemia (HLP) has developed into a high incidence disease that seriously threatens human health. Finding a new target for effective treatment of HLP will be a powerful way to reduce the incidence of CVD. The purpose of this study was to find potential biomarkers in urine of HLP patients and analyze their metabolic pathways to study the pathogenesis of HLP. METHODS An UPLC-Q-TOF/MS technology was used to detect the metabolites in urine of 60 HLP patients and 60 normal controls. Based on PLS-DA pattern recognition, potential biomarkers related to HLP were screened out. RESULTS 22 potential biomarkers related to HLP were identified, which involved amino acid metabolism, fatty acid metabolism, nucleotide metabolism, steroid hormone metabolism and intestinal flora metabolism, and their possible pathogenesis was found to be related to inflammatory reaction and oxidative stress. CONCLUSION The non-targeted metabolomic method based on UPLC-Q-TOF/MS technology can effectively identify potential biomarkers in the urine of HLP patients and explore the possible pathogenesis. Our research will lay a foundation for finding new targets for the treatment of HLP and provide a basis for clinical research on the treatment of HLP.
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Affiliation(s)
- Liu Yang
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Zhu Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Yanqi Song
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Yijia Liu
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Huan Zhao
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Yuechen Liu
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Tianpu Zhang
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Yu Yuan
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Xuemeng Cai
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Shuo Wang
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Pengwei Wang
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Shan Gao
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China
| | - Lin Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China.
| | - Yubo Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China.
| | - Chunquan Yu
- Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China.
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Komnenov D, Levanovich PE, Rossi NF. Hypertension Associated with Fructose and High Salt: Renal and Sympathetic Mechanisms. Nutrients 2019; 11:nu11030569. [PMID: 30866441 PMCID: PMC6472002 DOI: 10.3390/nu11030569] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/26/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023] Open
Abstract
Hypertension is a leading cause of cardiovascular and chronic renal disease. Despite multiple important strides that have been made in our understanding of the etiology of hypertension, the mechanisms remain complex due to multiple factors, including the environment, heredity and diet. This review focuses on dietary contributions, providing evidence for the involvement of elevated fructose and salt consumption that parallels the increased incidence of hypertension worldwide. High fructose loads potentiate salt reabsorption by the kidney, leading to elevation in blood pressure. Several transporters, such as NHE3 and PAT1 are modulated in this milieu and play a crucial role in salt-sensitivity. High fructose ingestion also modulates the renin-angiotensin-aldosterone system. Recent attention has been shifted towards the contribution of the sympathetic nervous system, as clinical trials demonstrated significant reductions in blood pressure following renal sympathetic nerve ablation. New preclinical data demonstrates the activation of the renal sympathetic nerves in fructose-induced salt-sensitive hypertension, and reductions of blood pressure after renal nerve ablation. This review further demonstrates the interplay between sodium handling by the kidney, the renin-angiotensin-aldosterone system, and activation of the renal sympathetic nerves as important mechanisms in fructose and salt-induced hypertension.
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Affiliation(s)
- Dragana Komnenov
- Department of Physiology, Wayne State University, 4160 John R Street #908, Detroit, MI 48201, USA.
- Department of Internal Medicine, Wayne State University, 4160 John R Street #908, Detroit, MI 48201, USA.
| | - Peter E Levanovich
- Department of Physiology, Wayne State University, 4160 John R Street #908, Detroit, MI 48201, USA.
| | - Noreen F Rossi
- Department of Physiology, Wayne State University, 4160 John R Street #908, Detroit, MI 48201, USA.
- Department of Internal Medicine, Wayne State University, 4160 John R Street #908, Detroit, MI 48201, USA.
- John D. Dingell VA Medical Center, 4646 John R Street, Detroit, MI 48201, USA.
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David J, Dardevet D, Mosoni L, Savary-Auzeloux I, Polakof S. Impaired Skeletal Muscle Branched-Chain Amino Acids Catabolism Contributes to Their Increased Circulating Levels in a Non-Obese Insulin-Resistant Fructose-Fed Rat Model. Nutrients 2019; 11:E355. [PMID: 30744017 PMCID: PMC6412955 DOI: 10.3390/nu11020355] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 02/04/2019] [Accepted: 02/05/2019] [Indexed: 12/11/2022] Open
Abstract
Elevated plasma branched-chain amino acids (BCAA) levels are often observed in obese insulin-resistant (IR) subjects and laboratory animals. A reduced capacity of the adipose tissues (AT) to catabolize BCAA has been proposed as an explanation, but it seems restricted to obesity models of genetically modified or high fat⁻fed rodents. We aimed to determine if plasma BCAA levels were increased in a model of IR without obesity and to explore the underlying mechanisms. Rats were fed with a standard diet, containing either starch or fructose. BCAA levels, body weight and composition were recorded before and after 5, 12, 30, or 45 days of feeding. Elevated blood BCAA levels were observed in our IR model with unaltered body weight and composition. No changes were observed in the liver or the AT, but instead an impaired capacity of the skeletal muscle to catabolize BCAA was observed, including reduced capacity for transamination and oxidative deamination. Although the elevated blood BCAA levels in the fructose-fed rat seem to be a common feature of the IR phenotype observed in obese subjects and high fat⁻fed animals, the mechanisms involved in such a metabolic phenomenon are different, likely involving the skeletal muscle BCAA metabolism.
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Affiliation(s)
- Jérémie David
- Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, F-63000 CLERMONT-FERRAND, France.
| | - Dominique Dardevet
- Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, F-63000 CLERMONT-FERRAND, France.
| | - Laurent Mosoni
- Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, F-63000 CLERMONT-FERRAND, France.
| | - Isabelle Savary-Auzeloux
- Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, F-63000 CLERMONT-FERRAND, France.
| | - Sergio Polakof
- Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, F-63000 CLERMONT-FERRAND, France.
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Surowska A, Jegatheesan P, Campos V, Marques AS, Egli L, Cros J, Rosset R, Lecoultre V, Kreis R, Boesch C, Pouymayou B, Schneiter P, Tappy L. Effects of Dietary Protein and Fat Content on Intrahepatocellular and Intramyocellular Lipids during a 6-Day Hypercaloric, High Sucrose Diet: A Randomized Controlled Trial in Normal Weight Healthy Subjects. Nutrients 2019; 11:nu11010209. [PMID: 30669704 PMCID: PMC6357079 DOI: 10.3390/nu11010209] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/14/2019] [Accepted: 01/15/2019] [Indexed: 01/11/2023] Open
Abstract
Sucrose overfeeding increases intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid concentrations in healthy subjects. We hypothesized that these effects would be modulated by diet protein/fat content. Twelve healthy men and women were studied on two occasions in a randomized, cross-over trial. On each occasion, they received a 3-day 12% protein weight maintenance diet (WM) followed by a 6-day hypercaloric high sucrose diet (150% energy requirements). On one occasion the hypercaloric diet contained 5% protein and 25% fat (low protein-high fat, LP-HF), on the other occasion it contained 20% protein and 10% fat (high protein-low fat, HP-LF). IHCL and IMCL concentrations (magnetic resonance spectroscopy) and energy expenditure (indirect calorimetry) were measured after WM, and again after HP-LF/LP-HF. IHCL increased from 25.0 ± 3.6 after WM to 147.1 ± 26.9 mmol/kg wet weight (ww) after LP-HF and from 30.3 ± 7.7 to 57.8 ± 14.8 after HP-LF (two-way ANOVA with interaction: p < 0.001 overfeeding x protein/fat content). IMCL increased from 7.1 ± 0.6 to 8.8 ± 0.7 mmol/kg ww after LP-HF and from 6.2 ± 0.6 to 6.9 ± 0.6 after HP-LF, (p < 0.002). These results indicate that liver and muscle fat deposition is enhanced when sucrose overfeeding is associated with a low protein, high fat diet compared to a high protein, low fat diet.
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Affiliation(s)
- Anna Surowska
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | | | - Vanessa Campos
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Anne-Sophie Marques
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Léonie Egli
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Jérémy Cros
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Robin Rosset
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Virgile Lecoultre
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Roland Kreis
- Department for Biomedical Research, University of Bern and Institute of Diagnostic Interventional and Pediatric Radiology, University Hospital, 3012 Bern, Switzerland.
| | - Chris Boesch
- Department for Biomedical Research, University of Bern and Institute of Diagnostic Interventional and Pediatric Radiology, University Hospital, 3012 Bern, Switzerland.
| | - Bertrand Pouymayou
- Department for Biomedical Research, University of Bern and Institute of Diagnostic Interventional and Pediatric Radiology, University Hospital, 3012 Bern, Switzerland.
| | - Philippe Schneiter
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
| | - Luc Tappy
- Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
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Effective Food Ingredients for Fatty Liver: Soy Protein β-Conglycinin and Fish Oil. Int J Mol Sci 2018; 19:ijms19124107. [PMID: 30567368 PMCID: PMC6321427 DOI: 10.3390/ijms19124107] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 12/15/2018] [Indexed: 02/06/2023] Open
Abstract
Obesity is prevalent in modern society because of a lifestyle consisting of high dietary fat and sucrose consumption combined with little exercise. Among the consequences of obesity are the emerging epidemics of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor that stimulates gene expression related to de novo lipogenesis in the liver. In response to a high-fat diet, the expression of peroxisome proliferator-activated receptor (PPAR) γ2, another nuclear receptor, is increased, which leads to the development of NAFLD. β-Conglycinin, a soy protein, prevents NAFLD induced by diets high in sucrose/fructose or fat by decreasing the expression and function of these nuclear receptors. β-Conglycinin also improves NAFLD via the same mechanism as for prevention. Fish oil contains n-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Fish oil is more effective at preventing NAFLD induced by sucrose/fructose because SREBP-1c activity is inhibited. However, the effect of fish oil on NAFLD induced by fat is controversial because fish oil further increases PPARγ2 expression, depending upon the experimental conditions. Alcohol intake also causes an alcoholic fatty liver, which is induced by increased SREBP-1c and PPARγ2 expression and decreased PPARα expression. β-Conglycinin and fish oil are effective at preventing alcoholic fatty liver because β-conglycinin decreases the function of SREBP-1c and PPARγ2, and fish oil decreases the function of SREBP-1c and increases that of PPARα.
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Intestinal Saturated Long-Chain Fatty Acid, Glucose and Fructose Transporters and Their Inhibition by Natural Plant Extracts in Caco-2 Cells. Molecules 2018; 23:molecules23102544. [PMID: 30301205 PMCID: PMC6222386 DOI: 10.3390/molecules23102544] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 09/29/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023] Open
Abstract
The intestinal absorption of fatty acids, glucose and fructose is part of the basic requirements for the provision of energy in the body. High access of saturated long-chain fatty acids (LCFA), glucose and fructose can facilitate the development of metabolic diseases, particularly the metabolic syndrome and type-2 diabetes mellitus (T2DM). Research has been done to find substances which decelerate or inhibit intestinal resorption of these specific food components. Promising targets are the inhibition of intestinal long-chain fatty acid (FATP2, FATP4), glucose (SGLT1, GLUT2) and fructose (GLUT2, GLUT5) transporters by plant extracts and by pure substances. The largest part of active components in plant extracts belongs to the group of polyphenols. This review summarizes the knowledge about binding sites of named transporters and lists the plant extracts which were tested in Caco-2 cells regarding uptake inhibition.
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31
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Lembede BW, Erlwanger KH, Nkomozepi P, Chivandi E. Terminalia Sericea aqueous leaf extract protects growing wistar rats against fructose-induced fatty liver disease. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2018; 16:jcim-2018-0035. [PMID: 29927747 DOI: 10.1515/jcim-2018-0035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 05/23/2018] [Indexed: 12/16/2022]
Abstract
Background Terminalia sericea (T. sericea) is traditionally used to treat stomach ailments, infections, hypertension and diabetes mellitus. Previous in vitro studies have reported that T. sericea has lipolytic properties. This study interrogated the effects of T. sericea on linear growth, development of fatty liver disease, viscera morphometry and health of growing rats fed a 12% fructose solution (FS). Methods Thirty 21-day old male Wistar rat pups were randomly allocated to five treatments: group I - plain gelatine cubes (PGC) + plain tap water (PW), group II - 12% FS + PGC, group III - gelatine cubes containing fenofibrate (Feno) at a dose of 100 mg/kg body + FS, group IV - gelatine cubes containing the low dose (100 mg/kg body mass per day) of the T. sericea extract (TsL) + FS, group V - gelatine cubes containing the high dose (400 mg/kg body mass per day) of the T. sericea extract (TsH) + FS. Following 12 weeks of feeding, the rats were fasted overnight, euthanized and plasma and viscera harvested for analysis. Results Consumption of fructose resulted in significantly increased (p<0.05) liver lipid content and caused macrovesicular steatosis. The T. sericea extracts at 400 mg/kg per day suppressed the fructose-induced liver lipid accumulation and macrovesicular steatosis similarly to 100 mg/kg per day of Feno. Conclusions These findings suggest that the aqueous T. sericea leaf extract at 400 mg/kg per day could potentially protect against fructose-induced lipid accumulation as well as macrovesicular steatosis.
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Affiliation(s)
- Busisani W Lembede
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg2193, Republic of South Africa
| | - Kennedy H Erlwanger
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg2193, Republic of South Africa
| | - Pilani Nkomozepi
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Doornfontein, Johannesburg, Republic of South Africa
| | - Eliton Chivandi
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg2193, Republic of South Africa
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Habitual Fructose Intake Relates to Insulin Sensitivity and Fatty Liver Index in Recent-Onset Type 2 Diabetes Patients and Individuals without Diabetes. Nutrients 2018; 10:nu10060774. [PMID: 29914103 PMCID: PMC6024554 DOI: 10.3390/nu10060774] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/07/2018] [Accepted: 06/13/2018] [Indexed: 12/16/2022] Open
Abstract
The association between the amount and sources of fructose intake with insulin sensitivity and liver fat needs further elucidation. This study aimed at examining whether habitual intake of sucrose plus non-sucrose bound as well as of non-sucrose bound fructose (total fructose, fruit-derived, juice-derived, sugar sweetened beverages (SSB)-derived fructose) is cross-sectionally associated with insulin sensitivity and fatty liver index (FLI). Fructose intake was estimated using the EPIC food frequency questionnaire from 161 participants with type 2 diabetes (T2D) in the ongoing German Diabetes Study (GDS) (age 53 ± 9 years; HbA1c 6.4 ± 0.9%) and 62 individuals without diabetes (CON) (47 ± 14 years; 5.3 ± 0.3%). Peripheral (M-value) and hepatic insulin resistance were assessed by hyperinsulinemic-euglycemic clamps with stable isotope dilution. FLI was calculated based on body mass index, waist circumference, triglyceride and gamma glutamyl transferase concentrations. Multivariable linear regression analyses were performed. A doubling of SSB-derived sucrose plus non-sucrose bound as well as of non-sucrose bound fructose intake was independently associated with a reduction of the M-value by −2.6% (−4.9; −0.2) and −2.7% (−5.2; −0.1) among T2D, respectively, with an increase in the odds of fatty liver by 16% and 17%, respectively among T2D (all p < 0.05). Doubling fruit-derived sucrose plus non-sucrose bound fructose intake independently related to a reduction in the odds of fatty liver by 13% (p = 0.033) among T2D. Moderate SSB-derived fructose intake may detrimentally affect peripheral insulin sensitivity, whereas fruit-derived fructose intake appeared beneficial for liver fat content.
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Crescenzo R, Cigliano L, Mazzoli A, Cancelliere R, Carotenuto R, Tussellino M, Liverini G, Iossa S. Early Effects of a Low Fat, Fructose-Rich Diet on Liver Metabolism, Insulin Signaling, and Oxidative Stress in Young and Adult Rats. Front Physiol 2018; 9:411. [PMID: 29755364 PMCID: PMC5932594 DOI: 10.3389/fphys.2018.00411] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 04/04/2018] [Indexed: 12/18/2022] Open
Abstract
The increase in the use of refined food, which is rich in fructose, is of particular concern in children and adolescents, since the total caloric intake and the prevalence of metabolic syndrome are increasing continuously in these populations. Nevertheless, the effects of high fructose diet have been mostly investigated in adults, by focusing on the effect of a long-term fructose intake. Notably, some reports evidenced that even short-term fructose intake exerts detrimental effects on metabolism. Therefore, the aim of this study was to compare the metabolic changes induced by the fructose-rich diet in rats of different age, i.e., young (30 days old) and adult (90 days old) rats. The fructose-rich diet increased whole body lipid content in adult, but not in young rats. The analysis of liver markers of inflammation suggests that different mechanisms depending on the age might be activated after the fructose-rich diet. In fact, a pro-inflammatory gene-expression analysis showed just a minor activation of macrophages in young rats compared to adult rats, while other markers of low-grade metabolic inflammation (TNF-alpha, myeloperoxidase, lipocalin, haptoglobin) significantly increased. Inflammation was associated with oxidative damage to hepatic lipids in young and adult rats, while increased levels of hepatic nitrotyrosine and ceramides were detected only in young rats. Interestingly, fructose-induced hepatic insulin resistance was evident in young but not in adult rats, while whole body insulin sensitivity decreased both in fructose-fed young and adult rats. Taken together, the present data indicate that young rats do not increase their body lipids but are exposed to metabolic perturbations, such as hepatic insulin resistance and hepatic oxidative stress, in line with the finding that increased fructose intake may be an important predictor of metabolic risk in young people, independently of weight status. These results indicate the need of corrective nutritional interventions for young people and adults as well for the prevention of fructose-induced metabolic alterations.
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Affiliation(s)
| | - Luisa Cigliano
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Arianna Mazzoli
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Rosa Cancelliere
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Rosa Carotenuto
- Department of Biology, University of Naples Federico II, Naples, Italy
| | | | - Giovanna Liverini
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Susanna Iossa
- Department of Biology, University of Naples Federico II, Naples, Italy
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Effect of high chronic intake of sucrose on liver metabolism in aging rats. Modulation by rutin and micronutrients. J Physiol Biochem 2018; 74:569-577. [DOI: 10.1007/s13105-018-0628-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 04/03/2018] [Indexed: 12/29/2022]
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Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest 2018; 128:545-555. [PMID: 29388924 DOI: 10.1172/jci96702] [Citation(s) in RCA: 354] [Impact Index Per Article: 50.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
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Affiliation(s)
- Sarah A Hannou
- Division of Endocrinology and Metabolism and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Danielle E Haslam
- Nutritional Epidemiology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA
| | - Nicola M McKeown
- Nutritional Epidemiology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA
| | - Mark A Herman
- Division of Endocrinology and Metabolism and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA
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Taskinen MR, Söderlund S, Bogl LH, Hakkarainen A, Matikainen N, Pietiläinen KH, Räsänen S, Lundbom N, Björnson E, Eliasson B, Mancina RM, Romeo S, Alméras N, Pepa GD, Vetrani C, Prinster A, Annuzzi G, Rivellese A, Després JP, Borén J. Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J Intern Med 2017; 282:187-201. [PMID: 28548281 DOI: 10.1111/joim.12632] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Overconsumption of dietary sugars, fructose in particular, is linked to cardiovascular risk factors such as type 2 diabetes, obesity, dyslipidemia and nonalcoholic fatty liver disease. However, clinical studies have to date not clarified whether these adverse cardiometabolic effects are induced directly by dietary sugars, or whether they are secondary to weight gain. OBJECTIVES To assess the effects of fructose (75 g day-1 ), served with their habitual diet over 12 weeks, on liver fat content and other cardiometabolic risk factors in a large cohort (n = 71) of abdominally obese men. METHODS We analysed changes in body composition, dietary intake, an extensive panel of cardiometabolic risk markers, hepatic de novo lipogenesis (DNL), liver fat content and postprandial lipid responses after a standardized oral fat tolerance test (OFTT). RESULTS Fructose consumption had modest adverse effects on cardiometabolic risk factors. However, fructose consumption significantly increased liver fat content and hepatic DNL and decreased β-hydroxybutyrate (a measure of β-oxidation). The individual changes in liver fat were highly variable in subjects matched for the same level of weight change. The increase in liver fat content was significantly more pronounced than the weight gain. The increase in DNL correlated positively with triglyceride area under the curve responses after an OFTT. CONCLUSION Our data demonstrated adverse effects of moderate fructose consumption for 12 weeks on multiple cardiometabolic risk factors in particular on liver fat content despite only relative low increases in weight and waist circumference. Our study also indicates that there are remarkable individual differences in susceptibility to visceral adiposity/liver fat after real-world daily consumption of fructose-sweetened beverages over 12 weeks.
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Affiliation(s)
- M-R Taskinen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki and Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - S Söderlund
- Research Programs Unit, Diabetes and Obesity, University of Helsinki and Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - L H Bogl
- Institute for Molecular Medicine FIMM, Helsinki, Finland.,Department of Public Health, University of Helsinki, Helsinki, Finland
| | - A Hakkarainen
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - N Matikainen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki and Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.,Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - K H Pietiläinen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki and Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.,Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - S Räsänen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki and Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - N Lundbom
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - E Björnson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - B Eliasson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - R M Mancina
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - S Romeo
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - N Alméras
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - G D Pepa
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - C Vetrani
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - A Prinster
- Biostructure and Bioimaging Institute, National Research Council, Naples, Italy
| | - G Annuzzi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - A Rivellese
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - J-P Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - J Borén
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
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Katsiki N, Purrello F, Tsioufis C, Mikhailidis DP. Cardiovascular disease prevention strategies for type 2 diabetes mellitus. Expert Opin Pharmacother 2017; 18:1243-1260. [DOI: 10.1080/14656566.2017.1351946] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Niki Katsiki
- Second Department of Propaedeutic Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Costas Tsioufis
- First Cardiology Clinic, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece
| | - Dimitri P. Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK
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Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, Spalding D. Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism 2017; 72:94-108. [PMID: 28641788 DOI: 10.1016/j.metabol.2017.04.011] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/11/2017] [Accepted: 04/23/2017] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
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Affiliation(s)
- Isabella Reccia
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Jayant Kumar
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Cherif Akladios
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Francesco Virdis
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Madhava Pai
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Nagy Habib
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Duncan Spalding
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
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40
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The Acute Effects of Simple Sugar Ingestion on Appetite, Gut-Derived Hormone Response, and Metabolic Markers in Men. Nutrients 2017; 9:nu9020135. [PMID: 28216550 PMCID: PMC5331566 DOI: 10.3390/nu9020135] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/07/2017] [Accepted: 02/08/2017] [Indexed: 11/17/2022] Open
Abstract
This pilot study aimed to investigate the effect of simple sugar ingestion, in amounts typical of common ingestion, on appetite and the gut-derived hormone response. Seven healthy men ingested water (W) and equicaloric solutions containing 39.6 g glucose monohydrate (G), 36 g fructose (F), 36 g sucrose (S), and 19.8 g glucose monohydrate + 18 g fructose (C), in a randomised order. Serum concentrations of ghrelin, glucose dependent insulinotropic polypeptide (GIP), glucagon like peptide-1 (GLP-1), insulin, lactate, triglycerides, non-esterified fatty acids (NEFA), and d-3 hydroxybutyrate, were measured for 60 min. Appetite was measured using visual analogue scales (VAS). The ingestion of F and S resulted in a lower GIP incremental area under the curve (iAUC) compared to the ingestion of G (p < 0.05). No differences in the iAUC for GLP-1 or ghrelin were present between the trials, nor for insulin between the sugars. No differences in appetite ratings or hepatic metabolism measures were found, except for lactate, which was greater following the ingestion of F, S, and C, when compared to W and G (p < 0.05). The acute ingestion of typical amounts of fructose, in a variety of forms, results in marked differences in circulating GIP and lactate concentration, but no differences in appetite ratings, triglyceride concentration, indicative lipolysis, or NEFA metabolism, when compared to glucose.
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Karise I, Ornellas F, Barbosa-da-Silva S, Matsuura C, Del Sol M, Aguila MB, Mandarim-de-Lacerda CA. Liver and Metformin: Lessons of a fructose diet in mice. BIOCHIMIE OPEN 2017; 4:19-30. [PMID: 29450137 PMCID: PMC5801827 DOI: 10.1016/j.biopen.2017.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/27/2017] [Indexed: 12/11/2022]
Abstract
Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with de novo lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases de novo lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states.
Fructose increases lipogenesis and lipid peroxidation, reduces the antioxidant defenses, and mitochondrial biogenesis. Metformin mechanism of action remains partially understood and controversial. Metformin can reverse the liver injury preventing the progression to more severe states.
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Affiliation(s)
- Iara Karise
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Fernanda Ornellas
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Sandra Barbosa-da-Silva
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Cristiane Matsuura
- Laboratory of Membrane Transport, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Mariano Del Sol
- Doctoral Programing on Morphological Sciences, Universidad de La Frontera, Temuco, Chile
| | - Marcia Barbosa Aguila
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.,Doctoral Programing on Morphological Sciences, Universidad de La Frontera, Temuco, Chile
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.,Doctoral Programing on Morphological Sciences, Universidad de La Frontera, Temuco, Chile
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Rippe JM, Sievenpiper JL, Lê KA, White JS, Clemens R, Angelopoulos TJ. What is the appropriate upper limit for added sugars consumption? Nutr Rev 2017; 75:18-36. [PMID: 27974597 PMCID: PMC5916235 DOI: 10.1093/nutrit/nuw046] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dramatic increases in obesity and diabetes have occurred worldwide over the past 30 years. Some investigators have suggested that these increases may be due, in part, to increased added sugars consumption. Several scientific organizations, including the World Health Organization, the Scientific Advisory Council on Nutrition, the Dietary Guidelines Advisory Committee 2015, and the American Heart Association, have recommended significant restrictions on upper limits of sugars consumption. In this review, the scientific evidence related to sugars consumption and its putative link to various chronic conditions such as obesity, diabetes, heart disease, nonalcoholic fatty liver disease, and the metabolic syndrome is examined. While it appears prudent to avoid excessive calories from sugars, the scientific basis for restrictive guidelines is far from settled.
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Affiliation(s)
- James M Rippe
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA.
| | - John L Sievenpiper
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Kim-Anne Lê
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - John S White
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Roger Clemens
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Theodore J Angelopoulos
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
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43
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Possibilities for the specific reduction of fructose. Eur Food Res Technol 2016. [DOI: 10.1007/s00217-016-2676-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Abdou RM, Zhu L, Baker RD, Baker SS. Gut Microbiota of Nonalcoholic Fatty Liver Disease. Dig Dis Sci 2016; 61:1268-81. [PMID: 26898658 DOI: 10.1007/s10620-016-4045-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/16/2016] [Indexed: 02/08/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease has been rapidly increasing worldwide. It has become a leading cause of liver transplantation. Accumulating evidence suggests a significant role for gut microbiota in its development and progression. Here we review the effect of gut microbiota on developing hepatic fatty infiltration and its progression. Current literature supports a possible role for gut microbiota in the development of liver steatosis, inflammation and fibrosis. We also review the literature on possible interventions for NAFLD that target the gut microbiota.
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Affiliation(s)
- Reham M Abdou
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA.
| | - Lixin Zhu
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA.,, 3435 Main Street, 413 Biomedical Research Building, Buffalo, NY, 14214, USA
| | - Robert D Baker
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA
| | - Susan S Baker
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA
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Surowska A, De Giorgi S, Theytaz F, Campos V, Hodson L, Stefanoni N, Rey V, Schneiter P, Laville M, Giusti V, Gabert L, Tappy L. Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism. Obesity (Silver Spring) 2016; 24:589-96. [PMID: 26916239 DOI: 10.1002/oby.21410] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 10/24/2015] [Accepted: 10/26/2015] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Fructose is partly metabolized in small bowel enterocytes, where it can be converted into glucose or fatty acids. It was therefore hypothesized that Roux-en-Y gastric bypass (RYGB) may significantly alter fructose metabolism. METHODS We performed a randomized clinical study in eight patients 12-17 months after RYGB and eight control (Ctrl) subjects. Each participant was studied after ingestion of a protein and lipid meal (PL) and after ingestion of a protein+lipid+fructose+glucose meal labeled with (13) C-fructose (PLFG). Postprandial blood glucose, fructose, lactate, apolipoprotein B48 (apoB48), and triglyceride (TG) concentrations, (13) C-palmitate concentrations in chylomicron-TG and VLDL-TG, fructose oxidation ((13) CO2 production), and gluconeogenesis from fructose (GNGf) were measured over 6 hours. RESULTS After ingestion of PLFG, postprandial plasma fructose, glucose, insulin, and lactate concentrations increased earlier and reached higher peak values in RYGB than in Ctrl. GNGf was 33% lower in RYGB than Ctrl (P = 0.041), while fructose oxidation was unchanged. Postprandial incremental areas under the curves for total TG and chylomicrons-TG were 72% and 91% lower in RYGB than Ctrl (P = 0.064 and P = 0.024, respectively). ApoB48 and (13) C-palmitate concentrations were not significantly different. CONCLUSIONS Postprandial fructose metabolism was not grossly altered, but postprandial lipid concentrations were markedly decreased in subjects having had RYGB surgery.
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Affiliation(s)
- Anna Surowska
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Sara De Giorgi
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Fanny Theytaz
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Vanessa Campos
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | | | - Valentine Rey
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | | | - Martine Laville
- Centre De Recherche En Nutrition Humaine Rhône Alpes, Centre Européen De Nutrition Pour La Santé, Hospices Civils De Lyon, Université Lyon 1, Pierre Bénite, France
| | - Vittorio Giusti
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Laure Gabert
- Centre De Recherche En Nutrition Humaine Rhône Alpes, Centre Européen De Nutrition Pour La Santé, Hospices Civils De Lyon, Université Lyon 1, Pierre Bénite, France
| | - Luc Tappy
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
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46
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Jegatheesan P, Beutheu S, Ventura G, Sarfati G, Nubret E, Kapel N, Waligora-Dupriet AJ, Bergheim I, Cynober L, De-Bandt JP. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease. Clin Nutr 2016; 35:175-182. [DOI: 10.1016/j.clnu.2015.01.021] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 12/29/2014] [Accepted: 01/29/2015] [Indexed: 02/07/2023]
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47
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Svihus B, Hervik AK. Digestion and metabolic fates of starch, and its relation to major nutrition-related health problems: A review. STARCH-STARKE 2016. [DOI: 10.1002/star.201500295] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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48
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Pierce AA, Duwaerts CC, Soon RK, Siao K, Grenert JP, Fitch M, Hellerstein MK, Beysen C, Turner SM, Maher JJ. Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury. J Nutr Biochem 2015; 29:12-20. [PMID: 26895660 DOI: 10.1016/j.jnutbio.2015.10.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 10/05/2015] [Accepted: 10/30/2015] [Indexed: 12/19/2022]
Abstract
Diets containing excess carbohydrate and fat promote hepatic steatosis and steatohepatitis in mice. Little is known, however, about the impact of specific carbohydrate/fat combinations on liver outcome. This study was designed to determine whether high-energy diets with identical caloric density but different carbohydrate and fat composition have unique effects on the liver. Four experimental diets were formulated with 60%kcal carbohydrate and 20%kcal fat, each in nearly pure form from a single source: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate. The diets were fed to mice for 3 or 12 weeks for analysis of lipid metabolism and liver injury. All mice developed hepatic steatosis over 12 weeks, but mice fed the sucrose-palmitate diet accumulated more hepatic lipid than those in the other three experimental groups. The exaggerated lipid accumulation in sucrose-palmitate-fed mice was attributable to a disproportionate rise in hepatic de novo lipogenesis. These mice accrued more hepatic palmitate and exhibited more evidence of liver injury than any of the other experimental groups. Interestingly, lipogenic gene expression in mice fed the custom diets did not correlate with actual de novo lipogenesis. In addition, de novo lipogenesis rose in all mice between 3 and 12 weeks, without feedback inhibition from hepatic steatosis. The pairing of simple sugar (sucrose) and saturated fat (palmitate) in a high-carbohydrate/moderate-fat diet induces more de novo lipogenesis and liver injury than other carbohydrate/fat combinations. Diet-induced liver injury correlates positively with hepatic de novo lipogenesis and is not predictable by isolated analysis of lipogenic gene expression.
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Affiliation(s)
- Andrew A Pierce
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0410, USA
| | - Caroline C Duwaerts
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0410, USA
| | - Russell K Soon
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0410, USA
| | - Kevin Siao
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0410, USA
| | - James P Grenert
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California San Francisco, San Francisco, CA 94143-0410, USA
| | - Mark Fitch
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA; KineMed, Inc., Emeryville, CA 94608, USA
| | - Marc K Hellerstein
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA; KineMed, Inc., Emeryville, CA 94608, USA
| | | | | | - Jacquelyn J Maher
- Liver Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0410, USA.
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Siddiqui RA, Xu Z, Harvey KA, Pavlina TM, Becker MJ, Zaloga GP. Comparative study of the modulation of fructose/sucrose-induced hepatic steatosis by mixed lipid formulations varying in unsaturated fatty acid content. Nutr Metab (Lond) 2015; 12:41. [PMID: 26583036 PMCID: PMC4650347 DOI: 10.1186/s12986-015-0038-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 11/08/2015] [Indexed: 12/18/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. The etiology of NAFLD remains unclear but is thought to relate to increased fatty acid flux within the liver that results in toxic fatty acid metabolite production. One source of increased fatty acid flux is fructose/sucrose-induced hepatic lipogenesis. Current treatment for NAFLD encompasses dietary modifications. However, little scientific evidence exists on which to base many dietary recommendations, especially the intake of different types of carbohydrates and fats. We hypothesized that lipid mixtures of unsaturated fatty acids would inhibit lipogenesis and subsequent hepatic steatosis induced by high carbohydrate diets. The aim of this study was to examine the effects of different complex mixtures of fatty acids upon the development of fructose/sucrose-induced hepatic steatosis. Methods C57BL/6 mice were randomized to normocaloric chow-based diets that varied in the type of carbohydrate (starch, sucrose, fructose). Animals in each carbohydrate group were further randomized to diets that varied in lipid type (no additional lipid, soybean oil, fish oil, olive/soybean oil, macadamia nut oil). These oils were chosen based upon their content of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, or omega-7 monounsaturated fatty acids. Fatty acid flux in the liver was determine by assessing hepatic lipid content (steatosis). We also assessed fatty acid levels in the plasma and liver of the animals, hepatic lipogenesis activity, hepatic stearoyl-CoA-1 desaturase activity, and hepatic elongase activity. Results Animals consumed similar amounts of the diets and maintained normal body weights throughout the study. Both sucrose and fructose induced hepatic lipogenesis and steatosis, with fructose being more potent. All mixed lipids similarly inhibited steatosis, limiting lipid content to levels found in the control (starch) animals. Lipogenesis and stearoyl-CoA-1 desaturase activity were increased in the sucrose and fructose groups. Levels of these enzymatic processes remained at baseline in all of the lipid groups. Conclusion This is the first study to compare various complex lipid mixtures, based upon dietary oils with different types of long-chain fatty acids, upon development of sucrose/fructose-induced steatosis. Both carbohydrate source and lipid content appear important for the modulation of steatosis. Moderate intake of complex lipids with high unsaturated to saturated fatty acid ratios inhibited both lipogenesis and steatosis.
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Affiliation(s)
- Rafat A Siddiqui
- Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave, Indianapolis, IN 46202 USA
| | - Zhidong Xu
- Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave, Indianapolis, IN 46202 USA
| | - Kevin A Harvey
- Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave, Indianapolis, IN 46202 USA
| | | | | | - Gary P Zaloga
- Baxter Healthcare Corporation, Deerfield, IL 60015 USA
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50
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De Stefanis D, Mastrocola R, Nigro D, Costelli P, Aragno M. Effects of chronic sugar consumption on lipid accumulation and autophagy in the skeletal muscle. Eur J Nutr 2015; 56:363-373. [PMID: 26487451 DOI: 10.1007/s00394-015-1086-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/13/2015] [Indexed: 12/23/2022]
Abstract
PURPOSE In recent years, the increasing consumption of soft drinks containing high-fructose corn syrup or sucrose has caused a rise in fructose intake, which has been related to the epidemic of metabolic diseases. As fructose and glucose intake varies in parallel, it is still unclear what the effects of the increased consumption of the two single sugars are. In the present study, the impact of chronic consumption of glucose or fructose on skeletal muscle of healthy mice was investigated. METHODS C57BL/6J male mice received water (C), 15 % fructose (ChF) or 15 % glucose (ChG) to drink for up to 7 months. Lipid metabolism and markers of inflammation and autophagy were assessed in gastrocnemius muscle. RESULTS Increased body weight and gastrocnemius muscle mass, as well as circulating glucose, insulin, and lipid plasma levels were observed in sugar-drinking mice. Although triglycerides increased in the gastrocnemius muscle of both ChF and ChG mice (+32 and +26 %, vs C, respectively), intramyocellular lipids accumulated to a significantly greater extent in ChF than in ChG animals (ChF +10 % vs ChG). Such perturbations were associated with increased muscle interleukin-6 levels (threefold of C) and with the activation of autophagy, as demonstrated by the overexpression of LC3B-II (ChF, threefold and ChG, twofold of C) and beclin-1 (ChF, sevenfold and ChG, tenfold of C). CONCLUSIONS The present results suggest that intramyocellular lipids and the pro-inflammatory signaling could contribute to the onset of insulin resistance and lead to the induction of autophagy, which could be an adaptive response to lipotoxicity.
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Affiliation(s)
- Daniela De Stefanis
- Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125, Turin, Italy
| | - Raffaella Mastrocola
- Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125, Turin, Italy.
| | - Debora Nigro
- Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125, Turin, Italy
| | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125, Turin, Italy.,Interuniversitary Institute of Myology, Chieti, Italy
| | - Manuela Aragno
- Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125, Turin, Italy
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