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Xu Y, Hsu MF, Haj FG, Vahmani P. Effects of beef fat enriched with trans vaccenic acid and cis9, trans11-CLA on glucose homoeostasis and hepatic lipid accumulation in high-fat diet-induced obese mice. Br J Nutr 2024; 131:1975-1984. [PMID: 38439535 PMCID: PMC11361915 DOI: 10.1017/s000711452400062x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/06/2024]
Abstract
Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.
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Affiliation(s)
- Yanqing Xu
- Department of Animal Science, University of California Davis, One Shields Ave, Davis, CA95616, USA
| | - Ming-Fo Hsu
- Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA95616, USA
| | - Fawaz George Haj
- Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA95616, USA
| | - Payam Vahmani
- Department of Animal Science, University of California Davis, One Shields Ave, Davis, CA95616, USA
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Chun HJ, Kim ER, Lee M, Choi DH, Kim SH, Shin E, Kim JH, Cho JW, Han DH, Cha BS, Lee YH. Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis. Metabolism 2023:155612. [PMID: 37277060 DOI: 10.1016/j.metabol.2023.155612] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 05/24/2023] [Accepted: 06/01/2023] [Indexed: 06/07/2023]
Abstract
AIMS Steatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH. MATERIALS AND METHODS Human liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, -fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day). RESULTS Liver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver. CONCLUSIONS This study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH by activating autophagy mediated by inhibition of hepatocellular glucose uptake and consequently decreasing intracellular O-GlcNAcylation.
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Affiliation(s)
- Hye Jin Chun
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Eun Ran Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.; Division of Endocrine and Kidney Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, Chungbuk 28159, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Da Hyun Choi
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Soo Hyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Eugene Shin
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jin-Hong Kim
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jin Won Cho
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea; Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul 03722, Republic of Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea..
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea..
| | - Yong-Ho Lee
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea..
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A high-fat, high-fructose diet induced hepatic steatosis, renal lesions, dyslipidemia, and hyperuricemia in non-obese rats. Heliyon 2022; 8:e10896. [PMID: 36247176 PMCID: PMC9562237 DOI: 10.1016/j.heliyon.2022.e10896] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/12/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022] Open
Abstract
Excessive consumption of fat and sugar is associated with various chronic diseases. However, the variation of fat and sugar content in the diet greatly affected the outcome. In this study, a high-fat, high-fructose diet (HFHFD) formula was made with a composition of 31.99% carbohydrate, 40.7% fat, 11.8% protein, and an additional 30% fructose drink to confirm the effects of HFHFD on metabolic health and pathological changes in organs, especially the liver, kidneys, pancreas, muscles, and spleen. A total of 24 male Wistar rats aged 8–12 weeks were divided into four groups: standard chow (SC), HFHFD, SC + carbon tetrachloride (CCl4), and HFHFD + CCl4. After eight weeks of dietary intervention, body mass index, obesity index, lipid profiles, liver function tests, fasting blood glucose, serum uric acid and urea levels, and tissue histopathology were examined. HFHFD with the main unsaturated fatty acids of linoleic acid (14.57%) and palmitoleic acid (8.28%), the main saturated fatty acids of stearic acid (13.62%) and myristic acid (10.09%), and a low trans-fatty acids content, did not promote the rats to become obese. However, liver histology examination showed severe hepatic steatosis (78.33%), leading to steatohepatitis accompanied by an increase in serum ALP (p < 0.01), triglyceride (p < 0.001), total cholesterol (p < 0.05), and uric acid (p < 0.001) levels. Other histological features showed moderate lesions (45%) of the kidney, slight vacuolization of the pancreas, and a mild increase of inflammatory cells in the spleen and muscle. So, this study found that although HFHFD did not promote obesity within 8 weeks of administration, it induced hepatic and renal lesions, dyslipidemia, and hyperuricemia as a metabolic consequence of excessive fatty acids and fructose.
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Shao G, Liu Y, Lu L, Zhang G, Zhou W, Wu T, Wang L, Xu H, Ji G. The Pathogenesis of HCC Driven by NASH and the Preventive and Therapeutic Effects of Natural Products. Front Pharmacol 2022; 13:944088. [PMID: 35873545 PMCID: PMC9301043 DOI: 10.3389/fphar.2022.944088] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a clinical syndrome with pathological changes that are similar to those of alcoholic hepatitis without a history of excessive alcohol consumption. It is a specific form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatocyte inflammation based on hepatocellular steatosis. Further exacerbation of NASH can lead to cirrhosis, which may then progress to hepatocellular carcinoma (HCC). There is a lack of specific and effective treatments for NASH and NASH-driven HCC, and the mechanisms of the progression of NASH to HCC are unclear. Therefore, there is a need to understand the pathogenesis and progression of these diseases to identify new therapeutic approaches. Currently, an increasing number of studies are focusing on the utility of natural products in NASH, which is likely to be a promising prospect for NASH. This paper reviews the possible mechanisms of the pathogenesis and progression of NASH and NASH-derived HCC, as well as the potential therapeutic role of natural products in NASH and NASH-derived HCC.
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Affiliation(s)
- Gaoxuan Shao
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Wang
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Pantaleão ACS, de Castro MP, Meirelles Araujo KSF, Campos CFF, da Silva ALA, Manso JEF, Machado JC. Ultrasound biomicroscopy for the assessment of early-stage nonalcoholic fatty liver disease induced in rats by a high-fat diet. Ultrasonography 2022; 41:750-760. [PMID: 35923118 PMCID: PMC9532208 DOI: 10.14366/usg.21182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 03/24/2022] [Indexed: 11/03/2022] Open
Abstract
PURPOSE The aim of this study was to assess the ability of ultrasound biomicroscopy (UBM) to diagnose the initial stages of nonalcoholic fatty liver disease (NAFLD) in a rat model. METHODS Eighteen male Wistar rats were allocated to control or experimental groups. A high-fat diet (HFD) with 20% fructose and 2% cholesterol, resembling a common Western diet, was fed to animals in the experimental groups for up to 16 weeks; those in the control group received a regular diet. A 21 MHz UBM system was used to acquire B-mode images at specific times: baseline (T0), 10 weeks (T10), and 16 weeks (T16). The sonographic hepatorenal index (SHRI), based on the average ultrasound image gray-level intensities from the liver parenchyma and right renal cortex, was determined at T0, T10, and T16. The liver specimen histology was classified using the modified Nonalcoholic Steatohepatitis Clinical Research Network NAFLD activity scoring system. RESULTS The livers in the animals in the experimental groups progressed from sinusoidal congestion and moderate macro- and micro-vesicular steatosis to moderate steatosis and frequent hepatocyte ballooning. The SHRI obtained in the experimental group animals at T10 and T16 was significantly different from the SHRI of pooled control group. No significant difference existed between the SHRI in animals receiving HFD between T10 and T16. CONCLUSION SHRI measurement using UBM may be a promising noninvasive tool to characterize early-stage NAFLD in rat models.
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Affiliation(s)
- Antonio Carlos Soares Pantaleão
- Post-graduate Program in Surgical Sciences, Department of Surgery, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | | | - André Luiz Alves da Silva
- Post-graduate Program in Surgical Sciences, Department of Surgery, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - José Eduardo Ferreira Manso
- Post-graduate Program in Surgical Sciences, Department of Surgery, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - João Carlos Machado
- Post-graduate Program in Surgical Sciences, Department of Surgery, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Biomedical Engineering Program-COPPE/Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Karkucinska-Wieckowska A, Simoes ICM, Kalinowski P, Lebiedzinska-Arciszewska M, Zieniewicz K, Milkiewicz P, Górska-Ponikowska M, Pinton P, Malik AN, Krawczyk M, Oliveira PJ, Wieckowski MR. Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship. Eur J Clin Invest 2022; 52:e13622. [PMID: 34050922 DOI: 10.1111/eci.13622] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023]
Abstract
According to the 'multiple-hit' hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro-oxidative (nitroso-oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.
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Affiliation(s)
| | - Ines C M Simoes
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Lebiedzinska-Arciszewska
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | | | - Paolo Pinton
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
| | - Afshan N Malik
- Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Marcin Krawczyk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, CIBB - Centre for Innovative Biomedicine and Biotechnology, Coimbra, Portugal
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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7
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Eng JM, Estall JL. Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol. Cells 2021; 10:cells10071805. [PMID: 34359974 PMCID: PMC8303413 DOI: 10.3390/cells10071805] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects approximately 1 in 4 people worldwide and is a major burden to health care systems. A major concern in NAFLD research is lack of confidence in pre-clinical animal models, raising questions regarding translation to humans. Recently, there has been renewed interest in creating dietary models of NAFLD with higher similarity to human diets in hopes to better recapitulate disease pathology. This review summarizes recent research comparing individual roles of major dietary components to NAFLD and addresses common misconceptions surrounding frequently used diet-based NAFLD models. We discuss the effects of glucose, fructose, and sucrose on the liver, and how solid vs. liquid sugar differ in promoting disease. We consider studies on dosages of fat and cholesterol needed to promote NAFLD versus NASH, and discuss important considerations when choosing control diets, mouse strains, and diet duration. Lastly, we provide our recommendations on amount and type of sugar, fat, and cholesterol to include when modelling diet-induced NAFLD/NASH in mice.
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Affiliation(s)
- James M. Eng
- Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC H2W 1R7, Canada;
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Jennifer L. Estall
- Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC H2W 1R7, Canada;
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
- Correspondence: ; Tel.: +1-(514)-987-5688
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8
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Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner. Nutrients 2021; 13:nu13051521. [PMID: 33946347 PMCID: PMC8145177 DOI: 10.3390/nu13051521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/16/2021] [Accepted: 04/23/2021] [Indexed: 11/17/2022] Open
Abstract
Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available “Western” diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.
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Peng C, Stewart AG, Woodman OL, Ritchie RH, Qin CX. Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments. Front Pharmacol 2020; 11:603926. [PMID: 33343375 PMCID: PMC7745178 DOI: 10.3389/fphar.2020.603926] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.
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Affiliation(s)
- Cheng Peng
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
| | - Alastair G Stewart
- Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia.,Australian Research Council, Centre for Personalised Therapeutics Technologies, Lancaster, CBR, Australia
| | - Owen L Woodman
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
| | - Cheng Xue Qin
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
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10
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Oteng AB, Kersten S. Mechanisms of Action of trans Fatty Acids. Adv Nutr 2020; 11:697-708. [PMID: 31782488 PMCID: PMC7231579 DOI: 10.1093/advances/nmz125] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/03/2019] [Accepted: 10/31/2019] [Indexed: 12/11/2022] Open
Abstract
Human studies have established a positive association between the intake of industrial trans fatty acids and the development of cardiovascular diseases, leading several countries to enact laws that restrict the presence of industrial trans fatty acids in food products. However, trans fatty acids cannot be completely eliminated from the human diet since they are also naturally present in meat and dairy products of ruminant animals. Moreover, bans on industrial trans fatty acids have not yet been instituted in all countries. The epidemiological evidence against trans fatty acids by far overshadows mechanistic insights that may explain how trans fatty acids achieve their damaging effects. This review focuses on the mechanisms that underlie the deleterious effects of trans fatty acids by juxtaposing effects of trans fatty acids against those of cis-unsaturated fatty acids and saturated fatty acids (SFAs). This review also carefully explores the argument that ruminant trans fatty acids have differential effects from industrial trans fatty acids. Overall, in vivo and in vitro studies demonstrate that industrial trans fatty acids promote inflammation and endoplasmic reticulum (ER) stress, although to a lesser degree than SFAs, whereas cis-unsaturated fatty acids are protective against ER stress and inflammation. Additionally, industrial trans fatty acids promote fat storage in the liver at the expense of adipose tissue compared with cis-unsaturated fatty acids and SFAs. In cultured hepatocytes and adipocytes, industrial trans fatty acids, but not cis-unsaturated fatty acids or SFAs, stimulate the cholesterol synthesis pathway by activating sterol regulatory element binding protein (SREBP) 2-mediated gene regulation. Interestingly, although industrial and ruminant trans fatty acids show similar effects on human plasma lipoproteins, in preclinical models, only industrial trans fatty acids promote inflammation, ER stress, and cholesterol synthesis. Overall, clearer insight into the molecular mechanisms of action of trans fatty acids may create new therapeutic windows for the treatment of diseases characterized by disrupted lipid metabolism.
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Affiliation(s)
- Antwi-Boasiako Oteng
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
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11
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Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Krag A, Karsdal MA, Nielsen MJ, Brockbank S, Cruwys S. Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2020; 318:G410-G418. [PMID: 31905026 DOI: 10.1152/ajpgi.00066.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.
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Affiliation(s)
- Samuel J Daniels
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark.,Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | | | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Maria F Bruun
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Sara T Hjuler
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark
| | - Kim Henriksen
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark
| | - Peter Hein
- Innovative Medicines Unit, Grünenthal, Aachen, Germany
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | | | | | | | - Simon Cruwys
- Innovative Medicines Unit, Grünenthal, Aachen, Germany
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12
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Simoes IC, Janikiewicz J, Bauer J, Karkucinska-Wieckowska A, Kalinowski P, Dobrzyń A, Wolski A, Pronicki M, Zieniewicz K, Dobrzyń P, Krawczyk M, Zischka H, Wieckowski MR, Potes Y. Fat and Sugar-A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease. Nutrients 2019; 11:2871. [PMID: 31771244 PMCID: PMC6950566 DOI: 10.3390/nu11122871] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD.
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Affiliation(s)
- Ines C.M. Simoes
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Justyna Janikiewicz
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Judith Bauer
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Biedersteiner Strasse 29, D-80802 Munich, Germany; (J.B.); (H.Z.)
| | | | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.K.); (K.Z.)
| | - Agnieszka Dobrzyń
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Andrzej Wolski
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Maciej Pronicki
- Department of Pathology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (A.K.-W.); (M.P.)
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.K.); (K.Z.)
| | - Paweł Dobrzyń
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Marcin Krawczyk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Medicine II, Saarland University Medical Center, 66421 Homburg, Germany
| | - Hans Zischka
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Biedersteiner Strasse 29, D-80802 Munich, Germany; (J.B.); (H.Z.)
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany
| | - Mariusz R. Wieckowski
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Yaiza Potes
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
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13
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Oteng A, Loregger A, van Weeghel M, Zelcer N, Kersten S. Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease. Mol Nutr Food Res 2019; 63:e1900385. [PMID: 31327168 PMCID: PMC6790681 DOI: 10.1002/mnfr.201900385] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/01/2019] [Indexed: 12/24/2022]
Abstract
SCOPE The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non-alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids. METHODS AND RESULTS Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element-binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage-activating protein (SCAP), yet independent of liver-X receptor and ubiquitin regulatory X domain-containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. CONCLUSION Elaidate induces cholesterogenesis in vitro by activating the SCAP-SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.
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Affiliation(s)
- Antwi‐Boasiako Oteng
- Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition and HealthWageningen University6708 WEWageningenThe Netherlands
| | - Anke Loregger
- Department of Medical BiochemistryAcademic Medical CenterUniversity of Amsterdam1105 AZAmsterdamThe Netherlands
| | - Michel van Weeghel
- Laboratory Genetic Metabolic DiseasesAmsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences1105 AZAmsterdamThe Netherlands
| | - Noam Zelcer
- Department of Medical BiochemistryAcademic Medical CenterUniversity of Amsterdam1105 AZAmsterdamThe Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition and HealthWageningen University6708 WEWageningenThe Netherlands
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14
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Boland ML, Oró D, Tølbøl KS, Thrane ST, Nielsen JC, Cohen TS, Tabor DE, Fernandes F, Tovchigrechko A, Veidal SS, Warrener P, Sellman BR, Jelsing J, Feigh M, Vrang N, Trevaskis JL, Hansen HH. Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source. World J Gastroenterol 2019; 25:4904-4920. [PMID: 31543682 PMCID: PMC6737317 DOI: 10.3748/wjg.v25.i33.4904] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/28/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The trans-fat containing AMLN (amylin liver non-alcoholic steatohepatitis, NASH) diet has been extensively validated in C57BL/6J mice with or without the Lepob/Lepob (ob/ob) mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH. Due to a recent ban on trans-fats as food additive, there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.
AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.
METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat (Primex shortening) substituted by equivalent amounts of palm oil [Gubra amylin NASH, (GAN) diet] for 8, 12 and 16 wk. C57BL/6J mice were fed the same diets for 28 wk. AMLN and GAN diets had similar caloric content (40% fat kcal), fructose (22%) and cholesterol (2%) level.
RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance. Biopsy-confirmed steatosis, lobular inflammation, hepatocyte ballooning, fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet. C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.
CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsy-confirmed NASH in ob/ob and C57BL/6J mice, making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.
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Affiliation(s)
- Michelle L Boland
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | - Denise Oró
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | | | | | | | - Taylor S Cohen
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - David E Tabor
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Fiona Fernandes
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Andrey Tovchigrechko
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | | | - Paul Warrener
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Bret R Sellman
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | | | | | - Niels Vrang
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | - James L Trevaskis
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
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15
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Ali Abd El-Aal Y, Mohamed Abdel-Fattah D, El-Dawy Ahmed K. Some biochemical studies on trans fatty acid-containing diet. Diabetes Metab Syndr 2019; 13:1753-1757. [PMID: 31235089 DOI: 10.1016/j.dsx.2019.03.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
trans fatty acids (TFA's) are unsaturated fatty acid which have one or more double bond, they are present naturally and most of it is artificial, fried, baked food and margarine are major sources of TFA, there are several biological effects of TFAs on body health, various study showed that dietary TFA associated with various health disorders such as Diabetes, cardiovascular disease (CVD), Obesity, breast cancer, prostatic cancer infertility, and coronary artery disease (CAD). The World Health Organization (WHO) in 2015 encourages eliminations of trans fatty acids. The diet which related to non-communicable diseases include TFA should be eliminated, WHO's European Food and Nutrition Action Plan 2015-2020 suggested that TFAs should be less than 1% of the daily energy intake include natural origin. So the aim of this review, to know more than about trans acids, their nature, sources, and their different effect on health and how can analysis it.
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Affiliation(s)
- Yasmin Ali Abd El-Aal
- Biochemistry Department, Faculty of Applied Medical Science, October 6 University, Egypt.
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16
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Current Models of Fatty Liver Disease; New Insights, Therapeutic Targets and Interventions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:33-58. [PMID: 30919331 DOI: 10.1007/978-3-030-12668-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to steatosis with inflammation and fibrosis. NAFLD is currently the most prevalent chronic liver disease worldwide, with a global prevalence of 25%, and is soon projected to be the leading cause for liver transplantation in the US. Alarmingly, few effective pharmacotherapeutic approaches are currently available to block or attenuate development and progression of NAFLD. Preclinical models are critical for unraveling the complex and multi-factorial etiology of NAFLD and for testing potential therapeutics. Here we review preclinical models that have been instrumental in highlighting molecular and cellular mechanisms underlying the pathogenesis of NAFLD and in facilitating early proof-of-concept investigations into novel intervention strategies.
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17
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Mazidi M, Katsiki N, Mikhailidis DP, Banach M. Link between plasma trans-fatty acid and fatty liver is moderated by adiposity. Int J Cardiol 2018; 272:316-322. [PMID: 30072152 DOI: 10.1016/j.ijcard.2018.07.061] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 06/16/2018] [Accepted: 07/11/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising. This increase may be associated with obesity. It has been suggested that trans-fatty acids (TFAs) play an important role in non-communicable diseases. AIM We examined the link between liver tests, fatty liver index (FLI) and plasma TFAs. Furthermore, we evaluated the impact of adiposity on this link. METHODS The National Health and Nutrition Examination Survey (NHANES) was used to obtain the data on TFAs and liver function biomarkers. We took account of complex NHANES data, masked variance and weighting methodology. RESULTS Of the 4252 participants, 46.4% were men. The mean age was 50.6 years overall; 51.3 years for men and 49.8 years for women (p = 0.206). In a fully adjusted model (demographic and clinical factors), FLI increased as trans-9-hexadecenoic acid and trans-11-octadecenoic acid levels increased; FLI was 38.1 and 42.3 for the first quarter (Q1) of trans-9-hexadecenoic acid and trans-11-octadecenoic acid, respectively, reaching 65.1 and 69.3 for the highest quarters (Q4) (p < 0.001 for all comparisons). Multivariable logistic regression showed for all four studied TFAs, the likelihood of NAFLD (determined by FLI) increased with increasing TFAs levels (quartiles) in a stepwise manner (p < 0.001 for all comparisons). Based on moderation analysis, a strong impact of body mass index (BMI) on the link between FLI and TFAs was observed. CONCLUSIONS Our results suggest a direct significant association between plasma TFAs, liver tests and NAFLD (assessed by FLI). Furthermore, BMI was shown to mediate this relationship. These findings highlight the importance of avoiding TFAs consumption in order to minimize cardiometabolic risk.
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Affiliation(s)
- Mohsen Mazidi
- Department of Biology and Biological Engineering, Food and Nutrition Science, Chalmers University of Technology, SE-41296 Gothenburg, Sweden.
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
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18
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Animal Models of Nonalcoholic Fatty Liver Disease-A Starter's Guide. Nutrients 2017; 9:nu9101072. [PMID: 28953222 PMCID: PMC5691689 DOI: 10.3390/nu9101072] [Citation(s) in RCA: 254] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/13/2017] [Accepted: 09/25/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.
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19
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Effect of a trans fatty acid-enriched diet on biochemical and inflammatory parameters in Wistar rats. Eur J Nutr 2016; 56:1003-1016. [PMID: 26754301 DOI: 10.1007/s00394-015-1148-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 12/22/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE Recent data regarding trans fatty acids (TFAs) have implicated these lipids as particularly deleterious to human health, causing systemic inflammation, endothelial dysfunction and possibly inflammation in the central nervous system (CNS). We aimed to clarify the impact of partially hydrogenated soybean oil (PHSO) with different TFA concentrations on cerebrospinal fluid (CSF), serum and hepatic parameters in adult Wistar rats. METHODS Wistar rats (n = 15/group) were fed either a normolipidic diet or a hyperlipidic diet for 90 days. The normolipidic and hyperlipidic diets had the same ingredients except for fat compositions, concentrations and calories. We used lard in the cis fatty acid group and PHSO in the trans fatty acid group. The intervention groups were as follows: (1) low lard (LL), (2) high lard (HL), (3) low partially hydrogenated soybean oil (LPHSO) and (4) high partially hydrogenated soybean oil (HPHSO). Body weight, lipid profiles and the inflammatory responses in the CSF, serum and liver tissue were analyzed. RESULTS Surprisingly, with the PHSO diet we observed a worse metabolic response that was associated with oxidative stress in hepatic tissue as well as impaired serum and CSF fluid parameters at both PHSO concentrations. In many analyses, there were no significant differences between the LPHSO and HPHSO diets. CONCLUSIONS Dietary supplementation with PHSO impaired inflammatory parameters in CSF and blood, induced insulin resistance, altered lipid profiles and caused hepatic damage. Overall, these findings suggest that fat composition is more important than the quantity of fat consumed in terms of cis and trans fatty acid diets.
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20
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Koppe SWP. Obesity and the liver: nonalcoholic fatty liver disease. Transl Res 2014; 164:312-22. [PMID: 25028077 DOI: 10.1016/j.trsl.2014.06.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/18/2014] [Accepted: 06/19/2014] [Indexed: 02/08/2023]
Abstract
The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) parallels the rise of obesity and its complications. NAFLD is a common cause of cirrhosis and a leading indication for liver transplant. Genetic susceptibility, dietary composition, and exercise habits influence the development of NAFLD, and insulin resistance results in widespread metabolic perturbations with a net effect of triglyceride accumulation in the liver. Some patients will develop hepatocyte cellular injury and fibrosis of the liver, which can progress to cirrhosis and require liver transplant. Treatments targeting the pathophysiological mechanisms of NAFLD exist, but carry some potential risk and are not universally effective. Weight loss and lifestyle changes remain the most effective and safest approach, but sustainable change is difficult for most patients to achieve. Future work will continue to focus on developing effective and safe interventions to prevent the development of advanced liver disease, whereas efforts in the public health domain continue to combat obesity.
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Affiliation(s)
- Sean W P Koppe
- Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Ill.
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21
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Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten ELAF, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW. Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology 2013; 154:4536-47. [PMID: 24080367 PMCID: PMC4192287 DOI: 10.1210/en.2013-1592] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1(-/-), 5αR2(-/-), and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1(-/-) (but not 5αR2(-/-)) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2(-/-) and 0% of 5αR1(-/-) mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.
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Affiliation(s)
- Joanna K Dowman
- PhD, FRCP, Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom.
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22
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Neuschwander-Tetri BA, Ford DA, Acharya S, Gilkey G, Basaranoglu M, Tetri LH, Brunt EM. Dietary trans-fatty acid induced NASH is normalized following loss of trans-fatty acids from hepatic lipid pools. Lipids 2012; 47:941-50. [PMID: 22923371 PMCID: PMC3473077 DOI: 10.1007/s11745-012-3709-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Accepted: 07/27/2012] [Indexed: 12/13/2022]
Abstract
Previous experiments in mice showed that dietary trans-fats could play a role in non-alcoholic steatohepatitis (NASH) yet little is known about the accumulation trans-fats in hepatic lipid pools in relationship to liver injury. NASH is also associated with obesity yet improves with only modest weight loss. To distinguish the role of obesity versus sustained consumption of a trans-fat containing diet in causing NASH, mice with obesity and NASH induced by consuming a high trans-fat diet for 16 weeks were subsequently fed standard chow or maintained on trans-fat chow for another 8 weeks. The accumulation, partitioning and loss of trans-fats in the major hepatic lipid pools during and after trans-fat consumption were determined. Obese mice switched to standard chow remained obese but steatohepatitis improved. trans-fats were differentially incorporated into the major hepatic lipid pools and the loss of trans-fats after crossover to control chow was greatest in the cholesteryl ester pool. In summary, dietary changes can improve the biochemical and histopathological changes of NASH despite persistent obesity in mice. Analysis of hepatic lipids confirmed that dietary trans-fats accumulate in the major lipid pools and are released differentially with diet normalization. The substantial loss of trans-fats from the cholesteryl ester pool in parallel with improvement in NASH suggests that this pool of trans-fats could play a role in the pathogenesis of NASH.
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Affiliation(s)
- Brent A Neuschwander-Tetri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, Saint Louis, USA.
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Carvalhana S, Machado MV, Cortez-Pinto H. Improving dietary patterns in patients with nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012; 15:468-73. [PMID: 22878240 DOI: 10.1097/mco.0b013e3283566614] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is the liver epidemic of our time. Diet strongly influences its development and should be a component of any treatment plan. It is crucial to standardize diet recommendations in an evidence-based manner. RECENT FINDINGS Calorie restriction per se seems beneficial regardless of macronutrients composition. However, fat consumption, mainly cholesterol and saturated fatty acids are particularly steatogenic. There is increasing evidence that fructose, mainly consumed as soft drinks, is highly deleterious to the liver. Controversial results regarding modest alcohol consumption, suggest that although alcohol should not be advised, it should not be strictly forbidden. Recent studies suggest beneficial effects of coffee and tea in NAFLD. SUMMARY Patients with NAFLD should have an individualized diet recommendation, in order to lose at least 7% of their weight if overweight, reducing caloric intake, mainly at cost of cholesterol and saturated fatty acids. Simple sugars should be avoided, and soft drinks discouraged.
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Affiliation(s)
- Sofia Carvalhana
- Departamento de Gastrenterologia, Unidade de Nutrição e Metabolismo, Hospital Santa Maria, Faculdade de Medicina de Lisboa, Instituto de Medicina Molecular, Lisbon, Portugal
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24
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Effect of trans-fat, fructose and monosodium glutamate feeding on feline weight gain, adiposity, insulin sensitivity, adipokine and lipid profile. Br J Nutr 2012; 106:218-26. [PMID: 21429276 DOI: 10.1017/s000711451000588x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The incidence of obesity and type 2 diabetes mellitus (T2DM) is increasing, and new experimental models are required to investigate the diverse aspects of these polygenic diseases, which are intimately linked in terms of aetiology. Feline T2DM has been shown to closely resemble human T2DM in terms of its clinical, pathological and physiological features. Our aim was to develop a feline model of diet-induced weight gain, adiposity and metabolic deregulation, and to examine correlates of weight and body fat change, insulin homeostasis, lipid profile, adipokines and clinical chemistry, in order to study associations which may shed light on the mechanism of diet-induced metabolic dysregulation. We used a combination of partially hydrogenated vegetable shortening and high-fructose corn syrup to generate a high-fat-high-fructose diet. The effects of this diet were compared with an isoenergetic standard chow, either in the presence or absence of 1.125 % dietary monosodium glutamate (MSG). Dual-energy X-ray absorptiometry body imaging and a glucose tolerance test were performed. The present results indicate that dietary MSG increased weight gain and adiposity, and reduced insulin sensitivity (P < 0.05), whereas high-fat-high-fructose feeding resulted in elevated cortisol and markers of liver dysfunction (P < 0.01). The combination of all three dietary constituents resulted in lower insulin levels and elevated serum β-hydroxybutyrate and cortisol (P < 0.05). This combination also resulted in a lower first-phase insulin release during glucose tolerance testing (P < 0.001). In conclusion, markers of insulin deregulation and metabolic dysfunction associated with adiposity and T2DM can be induced by dietary factors in a feline model.
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25
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Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012; 15:374-80. [PMID: 22617564 PMCID: PMC3679496 DOI: 10.1097/mco.0b013e3283547157] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE OF REVIEW Obesity-associated nonalcoholic fatty liver disease (NAFLD) is highly prevalent, for which weight loss is the generally recommended clinical management. Low-carbohydrate ketogenic diets have been successful in promoting weight loss, but variations in the range of metabolic responses to these diets indicate that the effects of altering macronutrient content are not completely understood. This review focuses on the most recent findings that reveal the relationship between low-carbohydrate diets and NAFLD in rodent models and humans. RECENT FINDINGS Low-carbohydrate diets have been shown to promote weight loss, decrease intrahepatic triglyceride content, and improve metabolic parameters of patients with obesity. These ketogenic diets also provoke weight loss in rodents. However, long-term maintenance on a ketogenic diet stimulates the development of NAFLD and systemic glucose intolerance in mice. The relationship between ketogenic diets and systemic insulin resistance in both humans and rodents remains to be elucidated. SUMMARY Because low-carbohydrate ketogenic diets are increasingly employed for treatment of obesity, NAFLD, and neurological diseases such as epilepsy, understanding the long-term systemic effects of low-carbohydrate diets is crucial to the development of efficacious and safe dietary interventions.
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Affiliation(s)
- Rebecca C. Schugar
- Department of Medicine Center for Cardiovascular Research Washington University St. Louis, MO 63110 USA
| | - Peter A. Crawford
- Department of Medicine Center for Cardiovascular Research Washington University St. Louis, MO 63110 USA
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26
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Colak Y, Tuncer I, Senates E, Ozturk O, Doganay L, Yilmaz Y. Nonalcoholic fatty liver disease: a nutritional approach. Metab Syndr Relat Disord 2012; 10:161-166. [PMID: 22394108 DOI: 10.1089/met.2011.0145] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in many countries, and its prevalence is increasing. NAFLD is often considered to be a hepatic component of metabolic syndrome, and studies have established that insulin resistance plays a major role in the pathogenesis of NAFLD. Treatments for NAFLD primarily target insulin resistance. Interestingly, the most common environmental cause of insulin resistance is diet. This article examines the correlations between NAFLD and diet and provides some diet recommendations based on the most current data available.
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Affiliation(s)
- Yasar Colak
- Department of Gastroenterology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey.
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27
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Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 2012; 26:565-76. [PMID: 21947639 DOI: 10.1177/0884533611419668] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Worldwide, there is an epidemic of obesity and overweight, with two-thirds of Americans affected. A strong association exists between excessive body weight and nonalcoholic fatty liver disease (NAFLD), the most common etiology of abnormal liver function tests. Nonalcoholic fatty liver disease is a spectrum of liver disease, from a "bland" fatty infiltration to chronic hepatitis (nonalcoholic steatohepatitis or NASH), that can result in cirrhosis and organ failure. With the increasing prevalence of obesity in the world, the proportion of people affected by NAFLD is only expected to be parallel. Although primarily noted in obese individuals, NAFLD has also been associated with a number of surgical procedures, metabolic conditions, and medications. NASH is commonly underdiagnosed as most affected patients are symptom free, and routine screening is not performed. Noninvasive diagnostic testing is not sensitive in diagnosis or staging the severity of disease. Fatty infiltration and oxidative injury to the hepatocytes are believed to be the major factors behind the progression of disease from simple fatty infiltration of the liver to chronic hepatitis. Understanding the inflammatory pathways involved in NASH is a subject of extensive research. Currently, few proven treatment options exist, and controlled weight reduction is the only safe modality recommended for treatment of NASH.
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28
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Abstract
Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned.
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Affiliation(s)
- Jacquelyn J Maher
- Liver Center and Department of Medicine, University of California, San Francisco San Francisco, California, USA.
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29
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Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 2011; 300:G956-67. [PMID: 21454445 PMCID: PMC3119109 DOI: 10.1152/ajpgi.00539.2010] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 03/29/2011] [Indexed: 01/31/2023]
Abstract
Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.
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Affiliation(s)
- Joel R Garbow
- Department of 1Medicine, Washington University, St. Louis, Missouri 63110, USA
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30
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Bendsen NT, Chabanova E, Thomsen HS, Larsen TM, Newman JW, Stender S, Dyerberg J, Haugaard SB, Astrup A. Effect of trans fatty acid intake on abdominal and liver fat deposition and blood lipids: a randomized trial in overweight postmenopausal women. Nutr Diabetes 2011; 1:e4. [PMID: 23154296 PMCID: PMC3302130 DOI: 10.1038/nutd.2010.4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background: Intake of industrially produced trans fatty acids (TFAs) is, according to observational studies, associated with an increased risk of cardiovascular disease, but the causal mechanisms have not been fully elucidated. Besides inducing dyslipidemia, TFA intake is suspected to promote abdominal and liver fat deposition. Objective: We examined the effect of a high intake of TFA as part of an isocaloric diet on whole-body, abdominal and hepatic fat deposition, and blood lipids in postmenopausal women. Methods: In a 16-week double-blind parallel intervention study, 52 healthy overweight postmenopausal women were randomized to receive either partially hydrogenated soybean oil providing 15.7 g day−1 of TFA or a control oil with mainly oleic and palmitic acid. Before and after the intervention, body composition was assessed by dual-energy X-ray absorptiometry, abdominal fat by magnetic resonance (MR) imaging, and liver fat by 1H MR spectroscopy. Results: Compared with the control fat, TFA intake decreased plasma high-density lipoprotein (HDL)-cholesterol by 10%, increased low-density lipoprotein (LDL)-cholesterol by 18% and resulted in an increased LDL/HDL-cholesterol ratio (baseline adjusted mean (95% CI) difference between diet groups 0.41 (0.22; 0.60); P<0.001). TFA tended to increase the body fat (0.46 (−0.20; 1.17) kg; P=0.16) and waist circumference (1.1 (−0.1; 2.4) cm; P=0.08) more than the control fat, whereas neither abdominal nor liver fat deposition was affected by TFA. Conclusion: The adverse effect of dietary TFA on cardiovascular disease risk involves induction of dyslipidemia, and perhaps body fat, whereas weight gain-independent accumulation of ectopic fat could not be identified as a contributory factor during short-term intake.
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Affiliation(s)
- N T Bendsen
- Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark
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31
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Thompson AK, Minihane AM, Williams CM. Trans fatty acids, insulin resistance and diabetes. Eur J Clin Nutr 2010; 65:553-64. [DOI: 10.1038/ejcn.2010.240] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Obara N, Fukushima K, Ueno Y, Wakui Y, Kimura O, Tamai K, Kakazu E, Inoue J, Kondo Y, Ogawa N, Sato K, Tsuduki T, Ishida K, Shimosegawa T. Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice. J Hepatol 2010; 53:326-334. [PMID: 20462650 DOI: 10.1016/j.jhep.2010.02.029] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2009] [Revised: 01/18/2010] [Accepted: 02/26/2010] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Excessive trans-fatty acids (TFA) consumption has been thought to be a risk factor mainly for coronary artery diseases while less attention has been paid to liver disease. We aimed to clarify the impact of TFA-rich oil consumption on the hepatic pathophysiology compared to natural oil. METHODS Mice were fed either a low-fat (LF) or high-fat (HF) diet made of either natural oil as control (LF-C or HF-C) or partially hydrogenated oil, TFA-rich oil (LF-T or HF-T) for 24 weeks. We evaluated the liver and body weight, serological features, liver lipid content and composition, liver histology and hepatic lipid metabolism-related gene expression profile. In addition, primary cultures of mice Kupffer cells (KCs) were evaluated for cytokine secretion and phagocytotic ability after incubation in cis- or trans-fatty acid-containing medium. RESULTS The HF-T-fed mice showed significant increases of the liver and body weights, plasma alanine-aminotransferase, free fatty acid and hepatic triglyceride content compared to the HF-C group, whereas the LF-T group did not differ from the LF-C group. HF-T-fed mice developed severe steatosis, along with increased lipogenic gene expression and hepatic TFA accumulation. KCs showed increased tumor necrosis factor secretion and attenuated phagocytotic ability in the TFA-containing medium compared to its cis-isomer. CONCLUSIONS Excessive consumption of the TFA-rich oil up-regulated the lipogenic gene expression along with marked hepatic lipid accumulation. TFA might be pathogenic through causing severe steatosis and modulating the function of KCs. The quantity and composition of dietary lipids could be responsible for the pathogenesis of non-alcoholic steatohepatitis.
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Affiliation(s)
- Noriyuki Obara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574, Japan
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Abstract
Increasing rates of obesity have stimulated research into possible contributing factors, including specific dietary components such as trans fatty acids (TFAs). This review considers the evidence for an association between TFA intake and weight gain. It concludes that there is limited but consistent evidence from epidemiological studies, and from a primate model, that increased TFA consumption may result in a small additional weight gain. Data from a long-term study in a primate model suggest that TFA may have a greater adipogenic effect than cis monounsaturated fatty acids; however, there are currently inadequate mechanistic data to provide a comprehensive and plausible explanation for any such metabolic differences between the types of fatty acids.
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Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver-related risk, the latter regarding almost exclusively non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle-, drug- or surgically induced weight loss, insulin sensitizers, antioxidants, lipid-lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long-term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Liver biopsy remains the gold standard for staging NAFLD, but non-invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD-associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger- and longer-duration randomized trials assessing safety and benefits of drugs on patient-oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, Turin, Italy.
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35
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Abstract
PURPOSE OF REVIEW This review examines the effects of diet on nonalcoholic fatty liver disease (NAFLD). This includes the effects of calories, both in excess and restricted, as well as macronutrients. RECENT FINDINGS Recent findings suggest that short-term hypercaloric feeding leads to increased intrahepatic triglyceride (IHTG), whereas short-term hypocaloric feeding leads to decreased IHTG, despite little change in total body weight, suggesting that ongoing excess caloric delivery directly contributes to the development of NAFLD. Weight loss with either low-fat or low-carbohydrate diets can improve IHTG; however, specific macronutrients, such as fructose, trans-fatty acids, and saturated fat, may contribute to increased IHTG independent of total calorie intake. n-3 polyunsaturated fatty acids and monounsaturated fatty acids may play a protective role in NAFLD. The mechanisms behind these effects are not fully understood. SUMMARY Diet plays a role in the pathophysiology of NAFLD. It is reasonable to advise patients with NAFLD to reduce calorie intake with either low-fat or low-carbohydrate diets as well as limit intakes of fructose, trans-fatty acids, and saturated fat.
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36
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Abstract
Consumption of industrially produced trans-fatty acids (TFA) is associated with substantial risk of coronary heart disease (CHD). The magnitude of this relationship, as well as emerging associations with end points such as diabetes and sudden cardiac death, cannot be fully explained by the well-established adverse effects of TFA on serum lipids. We review the evidence for effects of TFA intake on nonlipid risk factors. Based on evidence from randomized controlled trials, observational studies, animal experiments, and in vitro studies, these include effects on systemic inflammation, endothelial dysfunction, visceral adiposity, insulin resistance, and arrhythmic risk. The types and strength of evidence for each of these nonlipid effects varies, but the overall constellation of findings is qualitatively and quantitatively unique among dietary fats. The multiple adverse effects and implicated pathways are consistent with the observed strong associations of TFA consumption with CHD risk. These nonlipid effects also explain why TFA consumption may adversely impact other non-CHD diseases and end points.
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Affiliation(s)
- Sarah K Wallace
- Department of Epidemiology, Harvard School of Public Health, Division of Cardiovascular Medicine and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Building 2-315, Boston, MA 02115, USA
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