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Fortes PC, Versari PH, Stinghen AE, Pecoits–Filho R. Controlling Inflammation in Peritoneal Dialysis: The Role of PD-Related Factors as Potential Intervention Targets. Perit Dial Int 2020. [DOI: 10.1177/089686080702702s14] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cardiovascular (CV) disease is the main cause of death in peritoneal dialysis (PD) patients, but the mechanisms mediating the increased CV risk observed in this group of patients are still largely unknown, which limits the perspective on effective therapeutic strategies. Patients on PD are already exposed to a number of traditional risk factors from the start of their chronic kidney disease (CKD), because many of those risk factors are common to CV disease and CKD alike. As renal dysfunction progresses, CKD-related risk factors are introduced, changing the profile of both the CV disease and the markers of risk. In this phase, which usually starts when glomerular filtration rate falls below 60 mL/min, the list of risk factors is expanded to include disturbances of mineral metabolism, anemia, fluid overload, uremic toxicity, and increased signs of oxidative stress and inflammation. Although many of the risk factors linked to CV burden are not related to the dialytic procedure, additional harm is introduced after the initiation of PD—with, for example, the presence of chronic infections and factors related to PD fluids, particularly reabsorption of glucose. In the present article, we review the impact of the novel risk factors introduced with the initiation of PD therapy, and we propose potential therapeutic strategies (which remain to be tested) for reducing CV mortality in this group of patients.
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Affiliation(s)
- Paulo C. Fortes
- Center for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
| | - Priscilla H. Versari
- Center for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
| | - Andréa E.M. Stinghen
- Center for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
| | - Roberto Pecoits–Filho
- Center for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
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Yu L, Gong L, Wang C, Hu N, Tang Y, Zheng L, Dai X, Li Y. Radix Polygoni Multiflori and Its Main Component Emodin Attenuate Non-Alcoholic Fatty Liver Disease in Zebrafish by Regulation of AMPK Signaling Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1493-1506. [PMID: 32346285 PMCID: PMC7167271 DOI: 10.2147/dddt.s243893] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 03/05/2020] [Indexed: 12/19/2022]
Abstract
Purpose Nonalcoholic fatty liver disease (NAFLD) has become a predictor of death in many diseases. This study was carried out to investigate the therapeutic effect of Radix Polygoni Multiflori Preparata (RPMP) and its main component emodin on egg yolk powder-induced NAFLD in zebrafish. Further investigation was performed to explore whether emodin was the main component of RPMP for the treatment of NAFLD as well as the underlying therapeutic mechanism of RPMP and emodin. Methods Zebrafish were divided into control group, egg yolk powder group, RPMP group and emodin group. The obesity of zebrafish was evaluated by body weight, body length and BMI. The content of lipid was detected by triglyceride (TG), total cholesterol (TC) reagent kit and the fatty acid was detected by nonesterified free fatty acids (NEFA) reagent kit. HE staining was used to detect the histological structure of liver. Whole-mount Oil red O staining and Frozen oil red O staining were carried out to investigate the lipid accumulation in liver. KEGG and STRING databases were performed to analyze the potential role of AMPK between insulin resistance (IR) and fatty acid oxidation. Western blot and RT-qPCR were carried out for mechanism research. Results RPMP and emodin significantly reduced zebrafish weight, body length and BMI. Both RPMP and emodin treatment could reduce the lipid deposition in zebrafish liver. RPMP significantly reduced the content of TG. However, emodin significantly reduced the contents of TG, TC and NEFA in zebrafish with NAFLD. The protein interaction network indicated that AMPK participated in both IR and fatty acid oxidation. Further investigation indicated that RPMP and emodin reduced hepatic lipogenesis via up-regulating the expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT2), amp-activated protein kinase alpha (AMPKα), proliferator-activated receptor alpha (PPARα), carnitine palmitoyl transferase 1a (CPT-1a) and acyl-coenzyme A oxidase 1 (ACOX1). Conclusion These findings suggest that emodin is the main component of RPMP for the treatment of NAFLD, which is closely related to the regulation of AMPK signaling pathway which increases IR and fatty acid oxidation.
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Affiliation(s)
- Linyuan Yu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Lihong Gong
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Cheng Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Naihua Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Yunqiu Tang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Li Zheng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Xuyang Dai
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
| | - Yunxia Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People's Republic of China
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Lee H, Kong G, Tran Q, Kim C, Park J, Park J. Relationship Between Ginsenoside Rg3 and Metabolic Syndrome. Front Pharmacol 2020; 11:130. [PMID: 32161549 PMCID: PMC7052819 DOI: 10.3389/fphar.2020.00130] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome is an important public health issue and is associated with a more affluent lifestyle. Many studies of metabolic syndrome have been reported, but its pathogenesis remains unclear and there is no effective treatment. The ability of natural compounds to ameliorate metabolic syndrome is currently under investigation. Unlike synthetic chemicals, such natural products have proven utility in various fields. Recently, ginsenoside extracted from ginseng and ginseng root are representative examples. For example, ginseng is used in dietary supplements and cosmetics. In addition, various studies have reported the effects of ginsenoside on metabolic syndromes such as obesity, diabetes, and hypertension. In this review, we describe the potential of ginsenoside Rg3, a component of ginseng, in the treatment of metabolic syndrome.
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Affiliation(s)
- Hyunji Lee
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Gyeyeong Kong
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Quangdon Tran
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Chaeyeong Kim
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Jisoo Park
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Life Science, Hyehwa Liberal Arts College, Daejeon University, Daejeon, South Korea
| | - Jongsun Park
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, South Korea.,Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, South Korea
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Coverdale JPC, Katundu KGH, Sobczak AIS, Arya S, Blindauer CA, Stewart AJ. Ischemia-modified albumin: Crosstalk between fatty acid and cobalt binding. Prostaglandins Leukot Essent Fatty Acids 2018; 135:147-157. [PMID: 30103926 PMCID: PMC6109191 DOI: 10.1016/j.plefa.2018.07.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/17/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis. "Ischemia-modified albumin" (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. More recent work suggested that Co2+ ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co2+ to sites A and/or B. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels.
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Affiliation(s)
| | - Kondwani G H Katundu
- School of Medicine, University of St Andrews, St Andrews, United Kingdom; College of Medicine, University of Malawi, Blantyre, Malawi
| | - Amélie I S Sobczak
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | - Swati Arya
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | | | - Alan J Stewart
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.
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Cholesterol-Lowering and Liver-Protective Effects of Cooked and Germinated Mung Beans ( Vigna radiata L.). Nutrients 2018; 10:nu10070821. [PMID: 29949855 PMCID: PMC6073478 DOI: 10.3390/nu10070821] [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: 06/06/2018] [Revised: 06/19/2018] [Accepted: 06/25/2018] [Indexed: 12/04/2022] Open
Abstract
We investigated the hypocholesterolemic and liver-protective effects of cooked and germinated whole mung beans. Hamsters were fed for 28 days on diets rich in saturated fatty acids and cholesterol, differing only in protein source (20%): casein, cooked whole mung bean, and germinated mung bean. After 28 days, we found reduced plasma concentrations of total cholesterol and non-HDL cholesterol, increased faecal cholesterol excretion, and reduced levels of asparagine aminotransferase and alanine aminotransferase enzymes in the liver. Reduction in hepatic lipid deposition was observed between each of the mung bean groups relative to the casein group. In addition, the animals of the geminated mung bean group showed a lack of inflammatory infiltrate and better vascularisation of the hepatic tissue. Results from this study show significant hypocholesterolemic and liver-protective properties of the mung bean, which are further enhanced after germination.
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Du J, Jia R, Cao LP, Ding W, Xu P, Yin G. Effects of Rhizoma Alismatis extract on biochemical indices and adipose gene expression in oleic acid-induced hepatocyte injury in Jian carp (Cyprinus carpio var. Jian). FISH PHYSIOLOGY AND BIOCHEMISTRY 2018; 44:747-768. [PMID: 29603076 DOI: 10.1007/s10695-017-0428-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 09/21/2017] [Indexed: 05/09/2023]
Abstract
Fatty liver is an increasingly serious disease of fish in aquaculture. However, the mechanisms responsible for the occurrence of fatty liver remain unclear, and no effective methods for the prevention and treatment of this disease have yet been found. In the present study, we aimed to develop an in vitro model of hepatocyte injury using oleic acid as hepatotoxicant and evaluate the protective effects of Rhizoma Alismatis extract (RAE) in Jian carp using this model. Primary hepatocytes from Jian carp were isolated and purified and cultured in vitro. The result indicated that 0.4 mmol L-1 oleic acid and 48 h could be the optimal conditions to induce hepatocyte injury model in cultured hepatocytes. Hepatocytes were exposed to oleic acid, followed by the addition of RAE at 0, 1, 5, 10, 20, or 50 μg mL-1. The hepatocytes and supernatant were then analyzed. RAE suppressed oleic acid-induced elevations in aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, lactate dehydrogenase, alkaline phosphatase, cholinesterase, malondialdehyde, γ-glutamyl transferase, cytochrome P450 1A, cytochrome P450 2E1, liver-type fatty acid binding protein, free fatty acid, fatty acid synthetase, and tumor necrosis factor-α (P < 0.01 or P < 0.05); reduced protein levels of cytochrome P450 1A, nuclear factor (NF)-κB p65, and NF-κB c-Rel; and inhibited cytochrome P4503A, NF-κB c-Rel, nuclear factor erythroid-related factor 2, peroxisome proliferator-activated receptor-α, and cytochrome P4501A mRNA levels. In conclusion, RAE exhibited a protective effect against hepatocyte injury in Jian carp. Further in vivo studies are needed to provide more evidence for the use of RAE as a hepatoprotective agent for the treatment of hepatocyte injury.
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Affiliation(s)
- Jinliang Du
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Li-Ping Cao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Weidong Ding
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| | - Guojun Yin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
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Im AR, Kim YH, Kim YH, Yang WK, Kim SH, Song KH. Dolichos lablab Protects Against Nonalcoholic Fatty Liver Disease in Mice Fed High-Fat Diets. J Med Food 2017; 20:1222-1232. [PMID: 29090980 DOI: 10.1089/jmf.2017.4036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hyacinth bean, Dolichos lablab or Lablab purpureus, has been used for centuries in India and China as an edible pod and animal forage, as well as to treat diarrhea and other gastrointestinal disease in traditional Korean medicine. Recently, we have demonstrated that D. lablab extract (DLL-Ex) prevented free fatty acid-induced lipid accumulation in an in vitro cellular nonalcoholic fatty liver disease (NAFLD) model. In this study, we, thus, aimed at clarifying the hepatoprotective effects of DLL-Ex in a high-fat diet-induced in vivo animal NAFLD model, as well as at elucidating underlying mechanisms of identified effects. Sixty, 6-week-old, male C57BL/6J mice were randomly divided into six groups: a control group fed a low-fat diet, four high-fat diet (HFD) groups, three receiving daily oral supplementation of DLL-Ex (25, 50, and 100 mg/kg/day), and one HFD group receiving daily oral supplementation of MILK (100 mg/kg/day). Effects of DLL-Ex supplementation were evaluated by histopathological and histochemical assessments. DLL-Ex supplementation inhibited HFD-induced increases in body weight and body fat mass and ameliorated increases in body weight, manifested as decreased liver function tests, lower serum triglycerides and cholesterol levels, and increased serum adiponectin levels. The expression of hepatic genes involved in lipid droplet accumulation and in fatty acid uptake was also decreased. We provide evidence of a protective effect of DLL-Ex against HFD-induced fatty liver disease in an animal model.
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Affiliation(s)
- A-Rang Im
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Yun Hee Kim
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Young Hwa Kim
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Won-Kyung Yang
- 2 Institute of Traditional Medicine and Bioscience, Daejeon University , Daejeon, Korea
| | - Seung Hyung Kim
- 2 Institute of Traditional Medicine and Bioscience, Daejeon University , Daejeon, Korea
| | - Kwang Hoon Song
- 3 Mibyeong Research Center, Korea Institute of Oriental Medicine , Daejeon, Korea.,4 University of Science and Technology , Daejeon, Korea
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Liver Enzymes and the Development of Posttransplantation Diabetes Mellitus in Renal Transplant Recipients. Transplant Direct 2017; 3:e208. [PMID: 28894795 PMCID: PMC5585424 DOI: 10.1097/txd.0000000000000717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/15/2017] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Posttransplantation diabetes mellitus (PTDM) is common in renal transplant recipients (RTR), increasing the risk of graft failure, cardiovascular disease, and mortality. Early detection of a high risk for PTDM is warranted. Because liver function and liver fat are involved, we investigated whether serum liver markers are associated with future PTDM in RTR. METHODS Between 2001 and 2003, 606 RTR with a functioning allograft beyond the first year after transplantation were included of which 500 participants (56% men; age, 50 ± 12 years) were free of diabetes at baseline and had liver enzyme values (1 missing) available. Serum concentrations of alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase were measured at baseline at 6.0 (6.2-11.5) years posttransplantation. PTDM cases were recorded until April 2012. RESULTS During median follow-up for 9.6 years (interquartile range [IQR], 6.2-10.2) beyond baseline, 76 (15.2%) patients developed PTDM. Comparing the highest to the lower tertiles, higher liver enzyme activities were significantly related to incident PTDM for ALT (hazard ratio [HR], 2.22; IQR, 1.42-3.48), for GGT (HR, 2.93; IQR, 1.87-4.61), and for alkaline phosphatase (HR, 1.78; IQR, 1.13-2.80). The associations of ALT and GGT with development of PTDM were independent of potential confounders and risk factors, including age, sex, renal function, medication use, lifestyle factors, adiposity, presence of the metabolic syndrome, fasting glucose, HbA1c, proinsulin, and cytomegalovirus status. CONCLUSIONS Markers for liver function and liver fat in the subclinical range are potential markers for future PTDM, independent of other known risk factors. This may allow for early detection and management of PTDM development.
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Im AR, Kim YH, Lee HW, Song KH. Water Extract of Dolichos lablab Attenuates Hepatic Lipid Accumulation in a Cellular Nonalcoholic Fatty Liver Disease Model. J Med Food 2017; 19:495-503. [PMID: 27152979 DOI: 10.1089/jmf.2015.3623] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is rising in prevalence worldwide. Therapeutic strategies for patients with NAFLD are limited by a lack of effective drugs. In this report, we show that Dolichos lablab water extract (DLL-Ex) protects against free fatty acid (FFA)-induced lipid accumulation and attenuates expression of genes involved in lipid droplet accumulation in cellular NAFLD models. The hepatoprotective effects and underlying mechanism of DLL-Ex were assessed using an in vitro cellular model in which NAFLD was simulated by inducing excessive FFA influx into hepatocytes. HepG2 cells were treated with DLL-Ex and FFAs for 24 h, after which intracellular lipid content was observed by using Nile Red and Oil Red O staining. Quantitative real-time polymerase chain reaction was used to measure expression levels of genes related to FFA-mediated cellular energy depletion. Western blotting was used to measure protein levels of phosphorylated c-Jun N-terminal kinase, AMP-activated protein kinase alpha (AMPKα), and peroxisome proliferator-activated receptor γ coactivator 1 alpha. In HepG2 cells, DLL-Ex inhibited expression of CD36, which regulates fatty acid uptake, as well as BODIPY-labeled fatty acid uptake. Additionally, DLL-Ex significantly attenuated FFA-mediated cellular energy depletion and mitochondrial membrane depolarization. Furthermore, DLL-Ex enhanced phosphorylation of AMPK, indicating that AMPK is a critical regulator of DLL-Ex-mediated inhibition of hepatic lipid accumulation, possibly through its antioxidative effect. These results demonstrate that DLL-Ex exerts potent anti-NAFLD activity, suggesting that it could be a potential adjuvant treatment for patients with NAFLD.
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Affiliation(s)
- A-Rang Im
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Yun Hee Kim
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Hye Won Lee
- 1 KM Convergence Research Division, Korea Institute of Oriental Medicine , Daejeon, Korea
| | - Kwang Hoon Song
- 2 Mibyeong Research Center, Korea Institute of Oriental Medicine , Daejeon, Korea.,3 University of Science and Technology , Daejeon, Korea
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Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines. BIOMED RESEARCH INTERNATIONAL 2015; 2015:414860. [PMID: 25922835 PMCID: PMC4397480 DOI: 10.1155/2015/414860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/19/2015] [Accepted: 03/10/2015] [Indexed: 02/08/2023]
Abstract
The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide) oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight) were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-α and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and sterol regulatory element-binding protein-1c (SREBP-1c) were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines.
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Emamgholipour S, Moradi N, Beigy M, Shabani P, Fadaei R, Poustchi H, Doosti M. The association of circulating levels of complement-C1q TNF-related protein 5 (CTRP5) with nonalcoholic fatty liver disease and type 2 diabetes: a case-control study. Diabetol Metab Syndr 2015; 7:108. [PMID: 26613006 PMCID: PMC4660841 DOI: 10.1186/s13098-015-0099-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 11/05/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is well-established that nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM). Complement-C1q TNF-related protein 5 (CTRP5) is a novel adipokine involved in the regulation of lipid and glucose metabolism. We aimed to assess plasma levels of CTRP5 in patients with NAFLD (n = 22), T2DM (n = 22) and NAFLD with T2DM (NAFLD + T2DM) (n = 22) in comparison with healthy subjects (n = 21) and also to study the association between CTRP5 levels and NAFLD and diabetes-related parameters. METHODS All subjects underwent anthropometric assessment, biochemical evaluation and liver stiffness (LS) measurement. Insulin resistance (IR) was determined by the homeostasis model assessment (HOMA). Plasma CTRP5 levels were measured by enzyme-linked immunosorbent assay. RESULTS We found significantly lower plasma levels of CTRP5 in patients with NAFLD + T2DM, NAFLD and T2DM (122.52 ± 1.92, 124.7 ± 1.82 and 118.31 ± 1.99 ng/ml, respectively) in comparison with controls (164.96 ± 2.95 ng/ml). In the whole study population, there was a significant negative correlations between CTRP5 and body mass index (r = -0.337; p = 0.002), fasting blood glucose (FBG) (r = -0.488; p < 0.001), triglyceride (TG) (r = -0.245; p = 0.031), HOMA-IR (r = -0.492; p < 0.001), insulin(r = -0.338; p = 0.002), LS (r = -0.544; p < 0.001), alanine aminotransferase (ALT) (r = -0.251; p = 0.027), waist-to-hip ratio (WHR) (r = -0.352; p = 0.002) and waist circumference (WC) (r = -0.357; p = 0.001). After adjustment for BMI, decrease in circulating levels of CTRP5 remained as a significant risk factor for NAFLD, T2DM and NAFLD + T2DM. The receiver operating characteristic (ROC) curves of circulating CTRP5 in predicting NAFLD and T2DM demonstrated an area under the curve (AUC) of 0.763 in T2DM, and 0.659 in NAFLD + T2DM. CONCLUSIONS It appears that the decreased levels of CTRP5 contribute to the increased risk of T2DM and NAFLD.
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Affiliation(s)
- Solaleh Emamgholipour
- />Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nariman Moradi
- />Department of Clinical Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maani Beigy
- />Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Shabani
- />Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Fadaei
- />Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- />Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Doosti
- />Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zhang J, Zhao Y, Xu C, Hong Y, Lu H, Wu J, Chen Y. Association between serum free fatty acid levels and nonalcoholic fatty liver disease: a cross-sectional study. Sci Rep 2014; 4:5832. [PMID: 25060337 PMCID: PMC5376058 DOI: 10.1038/srep05832] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 07/07/2014] [Indexed: 02/06/2023] Open
Abstract
High serum free fatty acid (FFA) levels are associated with metabolic syndrome (MS). This study aimed to assess the association of fasting serum FFAs with nonalcoholic fatty liver disease (NAFLD) in a Chinese population. A total of 840 subjects fulfilled the diagnostic criteria of NAFLD and 331 healthy control participants were enrolled in this cross-sectional study. Fasting serum FFA levels and other clinical and laboratory parameters were measured. NAFLD patients had significantly higher serum FFA levels than controls (P < 0.001). Serum FFA levels were significantly and positively correlated with parameters of MS, inflammation indexes, and markers of hepatocellular damage. Elevated serum FFA levels were found in NAFLD subjects with individual components of MS (obesity, hypertriglyceridaemia, and hyperglycaemia). Stepwise regression showed that serum FFA levels were an independent factor predicting advanced fibrosis (FIB-4 ≥ 1.3) in NAFLD patients. Serum FFA levels correlated with NAFLD and could be used as an indicator for predicting advanced fibrosis in NAFLD patients.
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Affiliation(s)
- Juanwen Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
- These authors contributed equally to this work
| | - Ying Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
- These authors contributed equally to this work
| | - Chengfu Xu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Yani Hong
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Huanle Lu
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Jianping Wu
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Yu Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
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Wang Y, Li J, Zhuge L, Su D, Yang M, Tao S, Li J. Comparison between the efficacies of curcumin and puerarin in C57BL/6 mice with steatohepatitis induced by a methionine- and choline-deficient diet. Exp Ther Med 2013; 7:663-668. [PMID: 24520264 PMCID: PMC3919823 DOI: 10.3892/etm.2013.1461] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Accepted: 12/03/2013] [Indexed: 01/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent disease, which features an abnormal accumulation of lipids inside hepatocytes. Steatohepatitis plays a critical role in the process resulting in liver fibrosis and cirrhosis. Curcumin and puerarin are herbal products widely used in Asia, which are believed to have therapeutic benefits for alleviating the symptoms of steatohepatitis. In this study, mice models of steatohepatitis induced by a methionine- and choline-deficient diet (MCD) were established to compare the pharmacological actions of curcumin and puerarin. The results showed that curcumin and puerarin exerted inhibitory effects against MCD-induced steatohepatitis in mice. Briefly, curcumin and puerarin significantly downregulated the levels of tumor necrosis factor-α in the blood serum of mice (P<0.01, versus the MCD group). In addition, the levels of triglycerides, total cholesterol and low density lipoproteins in the serum were significantly reduced by puerarin treatment (P<0.05, versus the MCD group). The concentration of interleukin-6 was downregulated by curcumin only (P<0.01, versus the MCD group). Curcumin and puerarin significantly increased the levels of peroxisome proliferator-activated receptor-γ (PPARγ; P<0.05, versus the MCD group). Moreover, increased nuclear factor-κB (NF-κB) was markedly attenuated by curcumin (P<0.05, versus the MCD group). In conclusion, curcumin and puerarin appear to exert different actions against steatohepatitis. It is possible that puerarin regulated lipid metabolism in the ‘first hit’ stage through the PPARγ pathway, while curcumin inhibited the inflammatory response in the ‘second hit’ stage through the NF-κB pathway.
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Affiliation(s)
- Yunliang Wang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
| | - Jian Li
- Preclinical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Li Zhuge
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
| | - Dongmei Su
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
| | - Meijuan Yang
- Preclinical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shiying Tao
- Preclinical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Junxiang Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
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Xin P, Han H, Gao D, Cui W, Yang X, Ying C, Sun X, Hao L. Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Food Chem Toxicol 2012; 52:12-8. [PMID: 23127599 DOI: 10.1016/j.fct.2012.10.026] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 10/10/2012] [Accepted: 10/23/2012] [Indexed: 10/27/2022]
Abstract
Lipid metabolic disorders are widely considered to be one of the most critical and basic link in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to illustrate the alleviation function of resveratrol (Res) on NAFLD and the roles of hepatic fatty acid synthase (FAS), low density lipoprotein receptor (LDLr), scavenger receptor class B type I (SR-BI), and thyroid hormone receptor β1 (TRβ1), which are the key molecules involved in lipid metabolism. Adult male Wistar rats were fed a normal diet or high fat/sucrose diet (HFS) with or without resveratrol for 13 weeks. HFS induced NAFLD formation and increased the lipids concentrations in serum and livers of rats, while noticeable improvement has been reached by Res intervention. Moreover, Res protected against HFS-induced decrease in hepatic LDLr and SR-BI mRNA and protein expressions, whereas TRβ1 expressions were impervious with/without Res. Unexpectedly, hepatic FAS gene expressions were markedly diminished in NAFLD rats and were gradually increased by treatment with Res. These data indicate that the alleviative effects of Res on NAFLD are associated with up regulation of hepatic LDLr and SR-BI gene expressions, which provide new insights into the pharmacological targets of Res in the prevention of NAFLD.
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Affiliation(s)
- Peng Xin
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, PR China
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Sparks JD, Sparks CE, Adeli K. Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Arterioscler Thromb Vasc Biol 2012; 32:2104-12. [PMID: 22796579 DOI: 10.1161/atvbaha.111.241463] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon feeding may be the first pathway to become resistant in obesity that leads to VLDL hypersecretion. This review summarizes the role of insulin-related signaling pathways that determine hepatic VLDL production. Disruption in signaling pathways that reduce generation of the second messenger phosphatidylinositide (3,4,5) triphosphate downstream of activated phosphatidylinositide 3-kinase underlies the development of VLDL hypersecretion. As insulin resistance progresses, a number of pathways are altered that further augment VLDL hypersecretion, including hepatic inflammatory pathways. Insulin plays a complex role in regulating glucose metabolism, and it is not surprising that the role of insulin in VLDL and lipid metabolism will prove equally complex.
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Affiliation(s)
- Janet D Sparks
- University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, Rochester, NY, USA
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Virgona N, Taki Y, Yamada S, Umegaki K. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. J Appl Toxicol 2012; 33:924-32. [PMID: 22729658 DOI: 10.1002/jat.2770] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 04/01/2012] [Accepted: 04/01/2012] [Indexed: 01/06/2023]
Abstract
Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0-0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3-weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies.
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Affiliation(s)
- Nantiga Virgona
- Information Center, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan
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Wang JK, Feng ZW, Li YC, Li QY, Tao XY. Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol 2012; 27:670-6. [PMID: 22097889 DOI: 10.1111/j.1440-1746.2011.06978.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Environmental and genetic factors play a role in the pathogenesis and natural history of non-alcoholic fatty liver disease (NAFLD). The objective of this study was to quantitatively evaluate the association between tumor necrosis factor (TNF)-α gene promoter polymorphism at sites -308 and -238 and NAFLD susceptibility. METHODS We performed an extensive search of relevant studies and made a meta-analysis, including eight studies with 837 NAFLD cases and 990 controls in the association between TNF-α -308 polymorphism and NAFLD; and seven studies with 771 cases and 787 controls in TNF-α -238 polymorphism. RESULTS The combined results showed that there was a significant difference in TNF-α-238 genotype distribution between NAFLD and control based on all studies (GA/AA vs GG [odds ratio = 2.06, 95% confidence interval = 1.58-2.69, P < 0.000,01]). However, the combined results based on all studies showed there was no evidence of association of TNF-α-308 genotype distribution between NAFLD cases and controls (GA/AA vs GG [odds ratio = 1.08, 95% confidence interval = 0.82-1.42, P = 0.60]). When stratifying for race, the significant results did not change materially compared with whole populations. CONCLUSION This meta-analysis suggested that TNF-α gene promoter polymorphism at position -238 but not -308 might be a risk factor for NAFLD.
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Affiliation(s)
- Ji-kai Wang
- School of Public Health, Anhui Medical University, Hefei, China
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Guo H, Li D, Ling W, Feng X, Xia M. Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ. J Lipid Res 2011; 52:908-22. [PMID: 21343633 DOI: 10.1194/jlr.m013375] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) controls the first step of triacylglycerol (TAG) synthesis and is critical to the understanding of chronic metabolic disorders such as primary nonalcoholic fatty liver disease (NAFLD). Anthocyanin, a large group of polyphenols, was negatively correlated with hepatic lipid accumulation, but its impact on mtGPAT1 activity and NAFLD has yet to be determined. Hepatoma cell lines and KKAy mice were used to investigate the impact of anthocyanin on high glucose-induced mtGPAT1 activation and hepatic steatosis. Treatment with anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g) reduced high glucose-induced GPAT1 activity through the prevention of mtGPAT1 translocation from the endoplasmic reticulum to the outer mitochondrial membrane (OMM), thereby suppressing intracellular de novo lipid synthesis. Cy-3-g treatment also increased protein kinase C ζ phosphorylation and membrane translocation in order to phosphorylate the mtF0F1-ATPase β-subunit, reducing its enzymatic activity and thus inhibiting mtGPAT1 activation. In vivo studies further showed that Cy-3-g treatment significantly decreases hepatic mtGPAT1 activity and its presence in OMM isolated from livers, thus ameliorating hepatic steatosis in diabetic KKAy mice. Our findings reveal a novel mechanism by which anthocyanin regulates lipogenesis and thereby inhibits hepatic steatosis, suggesting its potential therapeutic application in diabetes and related steatotic liver diseases.
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Affiliation(s)
- Honghui Guo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, PR China
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Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int 2010; 4:741-8. [PMID: 21286345 DOI: 10.1007/s12072-010-9202-6] [Citation(s) in RCA: 160] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Accepted: 07/12/2010] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The aim of this study was to explore the role of farnesoid X receptor (FXR) in liver lipid metabolism of non-alcoholic fatty liver disease (NAFLD) patients. METHODS In this study, pathology and clinical criteria confirmed NAFLD in patients. Fatty acid synthetase (FAS)-positive liver cells were visualized by laser scanning confocal microscopy. Levels of FXR, liver X receptor (LXR), sterol regulatory element binding protein 1C (SREBP-1C), and small heterodimer partner (SHP) proteins were detected by Western blot. FXR, LXR, and SHP mRNA levels were measured by real-time PCR. RESULTS In patients with NAFLD, a significant positive relationship between the degree of hepatic steatosis and serum triglycerides and cholesterol (correlation coefficient > 0.5, P < 0.05) was seen. The NAFLD patients had more FAS protein in liver, which suggests that there could have been more of fatty acid synthesis in hepatic cells (P < 0.05). The levels of FXR protein and mRNA were decreased in patients with NAFLD (P < 0.05), while those of LXR and SREBP-1C were increased (P < 0.05). The levels of SREBP-1C positively correlated with the degree of hepatic steatosis. There were no differences between the levels of SHP protein and mRNA both in NAFLD patients and normal controls (P > 0.05). CONCLUSION Our data showed that the decreased expression of hepatic FXR is associated with an increased expression of LXR, SREBP-1C, and hepatic triglyceride synthesis; furthermore, increased SREBP-1C is associated with the degree of hepatic steatosis in the NAFLD patients.
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Whitlock G. Commentary: Body weight and mortality in the late 19th century. Int J Epidemiol 2010; 39:959-63. [DOI: 10.1093/ije/dyq089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. Chem Biol Interact 2010; 184:376-87. [PMID: 20079722 DOI: 10.1016/j.cbi.2010.01.008] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2009] [Revised: 12/15/2009] [Accepted: 01/05/2010] [Indexed: 12/21/2022]
Abstract
Steatosis is the first step in the development of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms involved in its pathogenesis are not fully understood. Many nuclear receptors (NRs) involved in energy homeostasis and biotransformation constitute a network connecting fatty acids, cholesterol and xenobiotic metabolisms; therefore, multiple NRs and their ligands may play a prominent role in liver fat metabolism and accumulation. In this study we have attempted to gain insight into the relevance of the NR superfamily in NAFLD by investigating the steatogenic potential of 76 different NR ligands in fatty acid overloaded human hepatocytes and hepatoma cells. Moreover, we have determined the mRNA expression level of 24 NRs to correlate the steatogenic potential of the ligands with the expression of their associated NRs in the cultured cells. Our results demonstrate that 18% of the examined NR ligands enhanced lipid accumulation in human hepatocytes and/or hepatoma cells. Among them, ligands of PPARgamma (e.g., thiazolidinediones), LXR (paxilline and 24(S),25-epoxycholesterol), PXR (hyperforin), CAR (3alpha,5alpha-androstenol), ERalpha (tamoxifen), FXR (Z-guggulsterone), VDR (25-hydroxyvitamin D3) and particular retinoids and farnesoids showed a significant pro-steatotic effect. The mRNA level of most of the NRs examined was well preserved in human hepatocytes, but HepG2 showed a deranged profile, where many of the receptors had a marginal or negligible level of expression in comparison with the human liver. By comparing the steatogenic effect of NR ligands with the NR expression levels, we conclude that LXR, PXR, RAR and PPARgamma ligands likely induce fat accumulation by a NR-dependent mechanism. Indeed, over-expression of PXR in HepG2 cells enhanced the steatogenic effect of hyperforin and rifampicin. However, the accumulation of fat induced by other ligands did not correlate with the expression of their associated NR. Our results also suggest that human hepatocytes cultured with free fatty acids offer a highly valuable in vitro system to investigate the pathogenesis and therapeutics of the human fatty liver.
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Alanine aminotransferase and γ-glutamyltransferase as markers for elevated insulin resistance-associated metabolic abnormalities in obese Japanese men younger than 30 years of age. Obes Res Clin Pract 2010; 4:e1-e82. [DOI: 10.1016/j.orcp.2009.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2009] [Revised: 08/30/2009] [Accepted: 09/23/2009] [Indexed: 01/14/2023]
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Abstract
AIM: To investigate the association of fatty liver and smoking on metabolic syndrome and its components.
METHODS: This cross-sectional study enrolled participants who attended annual health screening at Shin Kong Wu Ho-Su Memorial Hospital from January to December 2005. A total of 3455 (1981 men and 1474 women) subjects were included in final analyses. Fatty liver was diagnosed using abdominal ultrasonography by trained gastroenterologists. The modified National Cholesterol Education Program Adult Treatment Panel III was used to define metabolic syndrome. The associations between smoking, fatty liver and metabolic syndrome were analyzed using multiple logistic regression.
RESULTS: Subjects with fatty liver, and who smoked tobacco, had the highest odds ratios (ORs) for high waist circumference [OR, 4.5 (95% CI: 3.3-6.1), P < 0.05], hypertriglyceridemia [OR, 8.1 (95% CI: 6.0-10.9), P < 0.05], low serum high-density lipoprotein cholesterol (HDL-C) [OR, 8.3 (95% CI: 6.1-11.3), P < 0.05], and metabolic syndrome [OR, 9.5 (95% CI: 6.7-13.4), P < 0.05] compared to subjects without fatty liver who did not smoke tobacco. We also found that the ORs for hypertriglyceridemia, low serum HDL-C, and metabolic syndrome for subjects with fatty liver who smoked tobacco had greater than the sum of the ORs for subjects with fatty liver who did not smoke plus those who did not have fatty liver and who did smoke.
CONCLUSION: Fatty liver and smoking had a synergistic effect on metabolic syndrome and its components, especially for hypertriglyceridemia and low serum HDL-C.
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Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373:1083-96. [PMID: 19299006 PMCID: PMC2662372 DOI: 10.1016/s0140-6736(09)60318-4] [Citation(s) in RCA: 3202] [Impact Index Per Article: 200.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies. METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other. FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI. INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained.
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Maglich JM, Lobe DC, Moore JT. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J Lipid Res 2008; 50:439-445. [PMID: 18941143 DOI: 10.1194/jlr.m800226-jlr200] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car(-/-) (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car(-/-) animals. Conversely, pharmacological induction of CAR activity using the selective mouse CAR agonist TCPOBOP during HFD feeding resulted in a CAR-dependent increase in serum triglyceride levels. A major regulator of hepatic fatty oxidation is the nuclear receptor PPARalpha (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPARalpha) target genes was inversely related to the activity of CAR. Consistent with these observations, Car(-/-) animals exhibited increased hepatic fatty acid oxidation. Treatment of mice with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) significantly decreased expression of PPARalpha mRNA as well as Cyp4a14, CPT1alpha, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH).
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Affiliation(s)
- Jodi M Maglich
- Metabolic Pathways, GlaxoSmithKline, Research Triangle Park, Durham, NC
| | - David C Lobe
- Metabolic Pathways, GlaxoSmithKline, Research Triangle Park, Durham, NC
| | - John T Moore
- Metabolic Pathways, GlaxoSmithKline, Research Triangle Park, Durham, NC.
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Abel T, Fehér J. [Non-alcoholic fatty liver disease and cardiovascular risk]. Orv Hetil 2008; 149:1299-305. [PMID: 18617457 DOI: 10.1556/oh.2008.28418] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Non-alcoholic fatty liver disease is present in 15-25% of the general population. The fundamental derangement in non-alcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, dyslipidemia, hypertension, and obesity. The natural history of non-alcoholic fatty liver disease is not always benign, and causality for chronic liver disease and cirrhosis is well known in clinical practice and sometimes it is accompanied by hepatocellular carcinoma. Non-alcoholic fatty liver disease is likely to be associated with increased cardiovascular disease risk, and it raises the possibility that non-alcoholic fatty liver disease may be not only a marker but also an early mediator of atherosclerosis. Therapy is currently directed at treating components of the metabolic syndrome which may be beneficial also for the liver.
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Affiliation(s)
- Tatjána Abel
- Allami Egészségügyi Központ Szakrendelo Intézet Budapest.
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Wang CC, Hsu CS, Liu CJ, Kao JH, Chen DS. Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis. J Gastroenterol Hepatol 2008; 23:779-82. [PMID: 18028349 DOI: 10.1111/j.1440-1746.2007.05216.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Chronic viral infections such as human immunodeficiency virus and hepatitis C virus (HCV) may decrease tissue response to insulin, thereby causing insulin resistance. In addition, insulin resistance is associated with hepatic steatosis. However, whether these phenomena hold true for chronic hepatitis B virus (HBV) infection remains largely unknown. The present study therefore aimed to investigate the association of chronic HBV infection with insulin resistance and hepatic steatosis. METHODS A total of 507 subjects (243 men and 264 women; mean age 46.56 years) less than 60 years-old attending a health examination center were enrolled in the study. All the subjects were negative for antibodies against HCV and consumed less than 140 g alcohol/week. Demographic, anthropometric, clinical, and laboratory data were obtained from each subject. Insulin resistance index was determined using homeostasis model assessment (HOMA-IR). Hepatic steatosis was identified by ultrasound examination. RESULTS Of the 507 subjects, 50 (9.9%) were positive for hepatitis B surface antigen (HBsAg) and designated HBV carriers. All variables were comparable between HBV carriers and non-HBV carriers, except that HBV carriers had significantly higher serum alanine aminotransferase and aspartate aminotransferase levels (P < 0.05). By multivariate linear regression, HBV carriers were not associated with insulin resistance. In addition, multivariate regression analyses showed that HBV carriers were not associated with the presence of ultrasonographic fatty liver. CONCLUSIONS Chronic HBV infection seems not to be associated with insulin resistance or hepatic steatosis in HBV carriers.
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Affiliation(s)
- Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
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Abstract
PURPOSE OF REVIEW One of the critical complications of obesity and diabetes is nonalcoholic fatty liver disease, a disorder of triacylglycerol accumulation in the liver that has potential to develop into end stage liver failure. In this review, the recent progress in understanding the role of hepatic triacylglycerol synthesis in the development of nonalcoholic fatty liver disease is discussed. RECENT FINDINGS It has become apparent that the development of hepatic steatosis is a complex, multifactorial process. Although the molecular pathways underlying its development have been described, there are no established therapies for nonalcoholic fatty liver disease. Recently, however, DGAT1 and DGAT2, the enzymes responsible for the final step in triacylglycerol synthesis, have been characterized as playing a vital role in hepatic triacylglycerol metabolism. Cellular and murine models in which diacylglycerol acyltransferase expression is altered suggest that these enzymes may play a role in the development hepatic steatosis, are feasible targets in the treatment of nonalcoholic fatty liver disease, but also function as lipotoxic buffers. SUMMARY Hepatic steatosis remains the watershed event in the progression of nonalcoholic fatty liver disease. The diacylglycerol acyltransferases are emerging as important mediators of hepatic triacylglycerol accumulation. Therefore, these enzymes are attractive targets in the development of therapies to prevent liver triacylglycerol accumulation and the consequences of nonalcoholic fatty liver disease.
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Affiliation(s)
- Aaron R Turkish
- Department of Pediatrics, Columbia University, New York, New York, USA.
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Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease is a common and serious form of chronic liver disease. It is characterized by lipid accumulation in the liver and is associated with all aspects - and may even be an initiating factor - of the metabolic syndrome. The purpose of this review is to summarize recent findings from human studies on dietary effects on hepatic lipid accumulation. RECENT FINDINGS Epidemiological studies did not give consistent results. From intervention studies there is evidence to support a role for weight loss. Some studies have also suggested that decreasing total fat intake and increasing the intake of fish oils may be beneficial in the treatment of nonalcoholic steatohepatitis. SUMMARY Only a few studies have focused on dietary effects on hepatic lipid accumulation. So far, there is only evidence to support a role for weight loss. Decreasing total fat intake and increasing the intake of fish oils may also be beneficial, but these conclusions are based on a limited number of studies, which sometimes lacked a proper control group. Also, other nutrients have not been studied in detail. Therefore, there is an urgent need for evidence-based dietary guidelines to prevent or even to treat nonalcoholic fatty liver disease.
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Affiliation(s)
- Ronald P Mensink
- Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
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Peroxisome proliferator-activated receptors and the metabolic syndrome. Physiol Behav 2007; 94:187-97. [PMID: 18191967 DOI: 10.1016/j.physbeh.2007.11.053] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2007] [Revised: 11/30/2007] [Accepted: 11/30/2007] [Indexed: 11/20/2022]
Abstract
The prevalence of the metabolic syndrome is rapidly increasing. This syndrome is characterized by metabolic disturbances, such as abnormal lipid and carbohydrate metabolism and a low-grade inflammatory state. PPARs play an important role in these metabolic processes, which makes them effective targets for treatment and prevention of the metabolic syndrome. Synthetic PPAR agonists, such as fibrates and thiazolidinediones are already used to treat hyperlipidemia and diabetes mellitus, respectively. Besides synthetic ligands, dietary fatty acids and fatty acid derivatives can also bind to an activate PPARs. As demonstrated with ligand-binding assays, PPARs have a clear preference of binding polyunsaturated fatty acids. Monounsaturated fatty acids are also very effective in binding PPARs, whereas saturated fatty acids are poor PPAR binders. However, ligand binding does not necessarily mean transcriptional activation. Therefore, it is important to investigate transactivation properties of dietary fatty acids as PPAR agonists and their role in metabolic reactions. Furthermore, human intervention studies comparing the effects of natural versus synthetic ligands side-by-side may reveal specific fatty acids that exert beneficial PPAR-mediated metabolic effects. The ability of PPARs to sense fatty acids and to mediate lipid metabolism, glucose metabolism and the inflammatory state makes them excellent targets for dietary modulation in order to prevent and treat the metabolic syndrome and associated diseases. This review discusses the role and function of PPARs and their ligands in light of the metabolic syndrome.
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Adiels M, Westerbacka J, Soro-Paavonen A, Häkkinen AM, Vehkavaara S, Caslake MJ, Packard C, Olofsson SO, Yki-Järvinen H, Taskinen MR, Borén J. Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia 2007; 50:2356-65. [PMID: 17849096 DOI: 10.1007/s00125-007-0790-1] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 06/21/2007] [Indexed: 12/11/2022]
Abstract
AIMS/HYPOTHESIS Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
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Affiliation(s)
- M Adiels
- Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Göteborg University, Gothenburg, Sweden
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Sookoian S, Castaño G, Gemma C, Gianotti TF, Pirola CJ. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J Gastroenterol 2007; 13:4242-8. [PMID: 17696255 PMCID: PMC4250625 DOI: 10.3748/wjg.v13.i31.4242] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity.
METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r2 > 0.8) were genotyped.
RESULTS: rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097).
CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.
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Affiliation(s)
- Silvia Sookoian
- Instituto de Investigaciones Medicas, A. Lanari. Universidad de Buenos Aires, CONICET, Combatiente de Malvinas 3150, 1427- Ciudad Autonoma de Buenos Aires, Argentina.
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Zivkovic AM, German JB, Sanyal AJ. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr 2007; 86:285-300. [PMID: 17684197 DOI: 10.1093/ajcn/86.2.285] [Citation(s) in RCA: 258] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant health problem and affects 70 million adults in the United States (30% of the adult population), and an estimated 20% of these individuals have the most severe form of NAFLD-nonalcoholic steatohepatitis (NASH). The mechanisms underlying disease development and progression are awaiting clarification. Insulin resistance and obesity-related inflammation, among other possible genetic, dietary, and lifestyle factors, are thought to play a key role. A program targeting gradual weight reduction and physical exercise continues to be the gold standard of treatment for all forms of NAFLD. Even though weight loss and dietary and lifestyle changes are recommended as primary treatment for fatty liver, little to no scientific evidence is available on diet and NAFLD. This article reviews the implications of current dietary approaches, including national guidelines and popular weight-loss diets, with a focus on determining the optimal diet to prescribe for NAFLD and NASH patients. The effects of macronutrient content (carbohydrate, fat, and protein ratios) and specific food components, such as soluble fiber, n-3 fatty acids, and fructose, are discussed. The premises, effects, barriers, and issues related to current dietary guidelines and specific diets are discussed, and the question, "Will it work for the pathogenesis of NAFLD and NASH? ", is addressed.
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Affiliation(s)
- Angela M Zivkovic
- Department of Food Science and Technology, University of California, Davis, CA 95616, USA.
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Suckling K. Drug discovery in the metabolic syndrome: context and some recent developments. Expert Opin Ther Targets 2007; 11:801-8. [PMID: 17504017 DOI: 10.1517/14728222.11.6.801] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The metabolic syndrome, encompassing the clinically distinct but related areas of dyslipidaemia, insulin resistance, obesity and vascular disease, offers a wide arena for drug discovery. There is substantial and growing unmet medical need, particularly as the worldwide epidemic of obesity continues to develop. There are also many targets and biological mechanisms that can be exploited. However, the context for clinical development is challenging because of the many ways in which the syndrome can be approached. As with most therapeutic areas, preclinical data provide only limited confidence in the potential of a novel target in humans. In this review, the author outlines the context for drug discovery in the metabolic syndrome, the clinical and biological scope and recent developments in preclinical models. Finally, existing examples of drug targets for a range of biological mechanisms are considered, outlining their biology and points relevant to lead identification and optimisation and clinical development.
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Moore C, Shen XD, Gao F, Busuttil RW, Coito AJ. Fibronectin-alpha4beta1 integrin interactions regulate metalloproteinase-9 expression in steatotic liver ischemia and reperfusion injury. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:567-77. [PMID: 17255325 PMCID: PMC1851880 DOI: 10.2353/ajpath.2007.060456] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ischemia/reperfusion injury is a major cause of the highly dysfunctional rate observed in marginal steatotic orthotopic liver transplantation. In this study, we document that the interactions between fibronectin, a key extracellular matrix protein, and its integrin receptor alpha4beta1, expressed on leukocytes, specifically up-regulated the expression and activation of metalloproteinase-9 (MMP-9, gelatinase B) in a well-established steatotic rat liver model of ex vivo ice-cold ischemia followed by isotransplantation. The presence of the active form of MMP-9 was accompanied by massive intragraft leukocyte infiltration, high levels of proinflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, and impaired liver function. Interestingly, MMP-9 activity in steatotic liver grafts was, to a certain extent, independent of the expression of its natural inhibitor, the tissue inhibitor of metalloproteinases-1. Moreover, the blockade of fibronectin-alpha4beta1-integrin interactions inhibited the expression/activation of MMP-9 in steatotic orthotopic liver transplantations without significantly affecting the expression of metalloproteinase-2 (MMP-2, gelatinase A). Finally, we identified T lymphocytes and monocytes/macrophages as major sources of MMP-9 in steatotic liver grafts. Hence, these findings reveal a novel aspect of the function of fibronectin-alpha4beta1 integrin interactions that holds significance for the successful use of marginal steatotic livers in transplantation.
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Affiliation(s)
- Carolina Moore
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7054, USA
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Diakou MC, Liberopoulos EN, Mikhailidis DP, Tsianos EV, Burroughs AK, Elisaf MS. Pharmacological treatment of non-alcoholic steatohepatitis: the current evidence. Scand J Gastroenterol 2007; 42:139-47. [PMID: 17327932 DOI: 10.1080/00365520601058395] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Maria C Diakou
- Department of Internal Medicine, Medical School, University of Ioannina, Greece
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Prevalencia, definición y manifestaciones clínicas del síndrome del ovario poliquístico. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/s1575-0922(06)71166-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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