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Wang J, Wen Y, Zhao W, Zhang Y, Lin F, Ouyang C, Wang H, Yao L, Ma H, Zhuo Y, Huang H, Shi X, Feng L, Lin D, Jiang B, Li Q. Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stress. eLife 2023; 12:RP87419. [PMID: 37902629 PMCID: PMC10615369 DOI: 10.7554/elife.87419] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023] Open
Abstract
Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However, how and where acetate is produced and the nature of its biological significance are largely unknown. We observed overproduction of acetate to concentrations comparable to those of ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT12 and ACOT8 are dramatically upregulated in the liver to convert free fatty acid-derived acetyl-CoA to acetate and CoA. This conversion not only provides a large amount of acetate, which preferentially fuels the brain rather than muscle, but also recycles CoA, which is required for sustained fatty acid oxidation and ketogenesis. We suggest that acetate is an emerging novel 'ketone body' that may be used as a parameter to evaluate the progression of energy stress.
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Affiliation(s)
- Jinyang Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Yaxin Wen
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Wentao Zhao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Yan Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Furong Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Cong Ouyang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Huihui Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Lizheng Yao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Huanhuan Ma
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Yue Zhuo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Huiying Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Xiulin Shi
- Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Province Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Liubin Feng
- High-Field NMR Center, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
| | - Donghai Lin
- Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
| | - Bin Jiang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Qinxi Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
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Tang G, Xu Y, Zhang C, Wang N, Li H, Feng Y. Green Tea and Epigallocatechin Gallate (EGCG) for the Management of Nonalcoholic Fatty Liver Diseases (NAFLD): Insights into the Role of Oxidative Stress and Antioxidant Mechanism. Antioxidants (Basel) 2021; 10:1076. [PMID: 34356308 PMCID: PMC8301033 DOI: 10.3390/antiox10071076] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/27/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.
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Affiliation(s)
- Guoyi Tang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (G.T.); (Y.X.); (C.Z.); (N.W.)
| | - Yu Xu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (G.T.); (Y.X.); (C.Z.); (N.W.)
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (G.T.); (Y.X.); (C.Z.); (N.W.)
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (G.T.); (Y.X.); (C.Z.); (N.W.)
| | - Huabin Li
- School of Public Health, Sun Yat-sen University, Guangzhou 510080, China;
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (G.T.); (Y.X.); (C.Z.); (N.W.)
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Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine. Sci Rep 2020; 10:5186. [PMID: 32198362 PMCID: PMC7083857 DOI: 10.1038/s41598-020-61869-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/24/2020] [Indexed: 12/15/2022] Open
Abstract
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
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Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 2017; 111:173-185. [PMID: 28109892 DOI: 10.1016/j.freeradbiomed.2017.01.023] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/11/2017] [Accepted: 01/15/2017] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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Affiliation(s)
- Francesco Bellanti
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Villani
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Antonio Facciorusso
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.
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Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, Spalding D. Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism 2017; 72:94-108. [PMID: 28641788 DOI: 10.1016/j.metabol.2017.04.011] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/11/2017] [Accepted: 04/23/2017] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
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Affiliation(s)
- Isabella Reccia
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Jayant Kumar
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Cherif Akladios
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Francesco Virdis
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Madhava Pai
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Nagy Habib
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Duncan Spalding
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
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González-Reimers E, Quintero-Platt G, Rodríguez-Gaspar M, Alemán-Valls R, Pérez-Hernández O, Santolaria-Fernández F. Liver steatosis in hepatitis C patients. World J Hepatol 2015; 7:1337-1346. [PMID: 26052379 PMCID: PMC4450197 DOI: 10.4254/wjh.v7.i10.1337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/31/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.
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Serviddio G, Bellanti F, Vendemiale G. Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radic Biol Med 2013; 65:952-968. [PMID: 23994574 DOI: 10.1016/j.freeradbiomed.2013.08.174] [Citation(s) in RCA: 205] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 08/20/2013] [Accepted: 08/20/2013] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
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Affiliation(s)
- Gaetano Serviddio
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
| | - Francesco Bellanti
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Parvy JP, Napal L, Rubin T, Poidevin M, Perrin L, Wicker-Thomas C, Montagne J. Drosophila melanogaster Acetyl-CoA-carboxylase sustains a fatty acid-dependent remote signal to waterproof the respiratory system. PLoS Genet 2012; 8:e1002925. [PMID: 22956916 PMCID: PMC3431307 DOI: 10.1371/journal.pgen.1002925] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Accepted: 07/13/2012] [Indexed: 02/07/2023] Open
Abstract
Fatty acid (FA) metabolism plays a central role in body homeostasis and related diseases. Thus, FA metabolic enzymes are attractive targets for drug therapy. Mouse studies on Acetyl-coenzymeA-carboxylase (ACC), the rate-limiting enzyme for FA synthesis, have highlighted its homeostatic role in liver and adipose tissue. We took advantage of the powerful genetics of Drosophila melanogaster to investigate the role of the unique Drosophila ACC homologue in the fat body and the oenocytes. The fat body accomplishes hepatic and storage functions, whereas the oenocytes are proposed to produce the cuticular lipids and to contribute to the hepatic function. RNA–interfering disruption of ACC in the fat body does not affect viability but does result in a dramatic reduction in triglyceride storage and a concurrent increase in glycogen accumulation. These metabolic perturbations further highlight the role of triglyceride and glycogen storage in controlling circulatory sugar levels, thereby validating Drosophila as a relevant model to explore the tissue-specific function of FA metabolic enzymes. In contrast, ACC disruption in the oenocytes through RNA–interference or tissue-targeted mutation induces lethality, as does oenocyte ablation. Surprisingly, this lethality is associated with a failure in the watertightness of the spiracles—the organs controlling the entry of air into the trachea. At the cellular level, we have observed that, in defective spiracles, lipids fail to transfer from the spiracular gland to the point of air entry. This phenotype is caused by disrupted synthesis of a putative very-long-chain-FA (VLCFA) within the oenocytes, which ultimately results in a lethal anoxic issue. Preventing liquid entry into respiratory systems is a universal issue for air-breathing animals. Here, we have shown that, in Drosophila, this process is controlled by a putative VLCFA produced within the oenocytes. Fatty acid homeostasis is deregulated in several human diseases, including obesity, diabetes, and most cancers. Therefore, the enzymes that catalyze the reactions of fatty acid metabolism constitute attractive targets for drug therapy. However, the development of novel inhibitors requires extensive analysis of the organ-specific functions of the targeted enzyme. Given the availability of genetic tools, the fruit fly Drosophila is an appropriate model system to investigate the physiological and developmental roles of metabolic enzymes. Here we studied a Drosophila homologue of a rate-limiting enzyme for fatty acid synthesis. We have shown that this enzyme is necessary to control the storage of lipids in the fat tissue, validating our system to study fatty acid metabolism. We further observed that this enzyme is essential in the oenocytes, a group of cells proposed to contribute to the hepatic function and to the formation of the cuticle. Furthermore, we have shown that a putative fatty acid produced in these cells is required to control, at a distance, the watertightness of the respiratory system. In summary, our study identifies a novel fatty acid-mediated signal necessary to prevent liquid accumulation in the respiratory system, a critical issue for all air-breathing animals.
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Affiliation(s)
- Jean-Philippe Parvy
- CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France
- Université Pierre et Marie Curie- Paris 6, Paris, France
| | - Laura Napal
- CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France
- Université Paris-Sud 11, Orsay, France
| | - Thomas Rubin
- CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France
- Université Paris-Sud 11, Orsay, France
| | - Mickael Poidevin
- CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France
- Université Paris-Sud 11, Orsay, France
| | | | | | - Jacques Montagne
- CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France
- Université Paris-Sud 11, Orsay, France
- * E-mail:
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Herman MA, Peroni OD, Villoria J, Schön MR, Abumrad NA, Blüher M, Klein S, Kahn BB. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 2012; 484:333-8. [PMID: 22466288 PMCID: PMC3341994 DOI: 10.1038/nature10986] [Citation(s) in RCA: 465] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 02/23/2012] [Indexed: 12/16/2022]
Abstract
The prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the Glut4-glucose transporter and alterations in adipose-Glut4 expression or function regulate systemic insulin sensitivity. Downregulation of adipose tissue-Glut4 occurs early in diabetes development. Here we report that adipose tissue-Glut4 regulates the expression of carbohydrate responsive-element binding protein (ChREBP), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose-ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We discovered a new mechanism for glucose-regulation of ChREBP: Glucose-mediated activation of the canonical ChREBP isoform (ChREBPα) induces expression of a novel, potent isoform (ChREBPβ) that is transcribed from an alternative promoter. ChREBPβ expression in human adipose tissue predicts insulin sensitivity indicating that it may be an effective target for treating diabetes.
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Affiliation(s)
- Mark A Herman
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Abstract
Intake of carbohydrates above the dietary guidelines to support performance of physical activity is common but may be unnecessary and counterproductive. Sports nutrition guidelines have not been designed to incorporate characteristics that may make high carbohydrate consumption a source of metabolic stress that may increase oxidative stress, inflammation, and lipogenesis. This metabolic stress is linked to the physiology underlying the development of insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. This review describes research-based evidence to aid in bridging the gap between dietary guidelines for overall health and those to support physical activity. Characteristics that increase the likelihood of metabolic stress resulting from carbohydrate intake include overweight and obesity, central/visceral adiposity, older age, sedentary lifestyle, and caloric state. Carbohydrate-based foods that provide the most health benefits are whole grains, beans and legumes, fruits, and vegetables. Carbohydrate-based foods that most readily elicit metabolic stress are those with added sugars and refined grains or that have a high glycemic index. A checklist that incorporates both the number of these characteristics and prevailing guidelines for nutrition and physical activity is presented. This may be useful in determining whether additional carbohydrates are needed to support the physical activity level of the individual.
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Affiliation(s)
- Mary P. Miles
- Department of Health and Human Development, Montana State University, Bozeman, Montana
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Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis. Chem Phys Lipids 2011; 164:500-14. [PMID: 21693109 DOI: 10.1016/j.chemphyslip.2011.06.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 06/04/2011] [Accepted: 06/06/2011] [Indexed: 01/12/2023]
Abstract
De novo fatty acid biosynthesis is also called lipogenesis. It is a metabolic pathway that provides the cells with fatty acids required for major cellular processes such as energy storage, membrane structures and lipid signaling. In this article we will review the role of the Liver X Receptors (LXRs), nuclear receptors that sense oxysterols, in the transcriptional regulation of genes involved in lipogenesis.
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12
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Amacher DE. The mechanistic basis for the induction of hepatic steatosis by xenobiotics. Expert Opin Drug Metab Toxicol 2011; 7:949-65. [PMID: 21510823 DOI: 10.1517/17425255.2011.577740] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Hepatic steatosis is the histological observation of numerous lipid inclusions due to an excess accumulation of triacylglycerols. They are a concern with new therapeutic candidates because they signify altered lipid metabolism that can progress to more serious liver toxicity. AREAS COVERED This article is based on an article search using the PubMed database from 1987 to 2011 and confirms associations for several previously marketed drugs with four basic hepatocellular mechanisms. The article also describes how these mechanisms are controlled by master regulators of lipid metabolism, which include gene transcription factors, nuclear receptors, hormonal signaling, energy sensing proteins, endoplasmic reticulum stress signaling and certain key metabolic intermediates. EXPERT OPINION Drug-induced hepatic steatosis is typically not detectable by conventional means other than invasive histological examinations. By understanding the basic mechanisms, key regulators and energy signaling systems of the liver, the investigator is better equipped to avoid xenobiotics with steatogenic potential in the drug discovery or early development process. There are now a number of methods for detecting this potential, specifically gene expression or metabolomic profiling and pathway analysis or mechanism-based in vitro systems.
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Pattullo V, Douglas MW, George J. Organelle dysfunction in hepatitis C virus-associated steatosis: anything to learn from nonalcoholic steatohepatitis? Expert Rev Gastroenterol Hepatol 2011; 5:265-77. [PMID: 21476921 DOI: 10.1586/egh.11.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) spans a pathological spectrum from nonalcoholic steatosis to steatohepatitis. The pathophysiology of this disorder is complex, but includes insulin resistance and disrupted lipid and carbohydrate homeostasis, which at a subcellular level results in oxidative stress, free fatty acid-mediated lipotoxicity, defects in mitochondrial function, endoplasmic reticulum stress and cytokine-mediated toxicity. In chronic hepatitis C (CHC), systemic metabolic derangements similar to NAFLD may be operative, but in addition, virus-specific factors contribute to steatosis. The mechanisms for steatosis in CHC appear to share common pathways with those observed in NAFLD. This article outlines our current understanding of the subcellular mechanisms of steatosis in NAFLD and CHC, including their similarities and differences.
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Affiliation(s)
- Venessa Pattullo
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Sydney, NSW 2145, Australia
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Pan Z, Wang J, Kang B, Lu L, Han C, Tang H, Li L, Xu F, Zhou Z, Lv J. Screening and identification of differentially expressed genes in goose hepatocytes exposed to free fatty acid. J Cell Biochem 2011; 111:1482-92. [PMID: 20872794 DOI: 10.1002/jcb.22878] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The overaccumulation of triglycerides in hepatocytes induces hepatic steatosis; however, little is known about the mechanism of goose hepatic steatosis. The aim of this study was to define an experimental model of hepatocellular steatosis with TG overaccumulation and minimal cytotoxicity, using a mixture of various proportions of oleate and palmitate free fatty acids (FFAs) to induce fat-overloading, then using suppressive subtractive hybridization and a quantitative PCR approach to identify genes with higher or lower expression levels after the treatment of cells with FFA mixtures. Overall, 502 differentially expressed clones, representing 21 novel genes and 87 known genes, were detected by SSH. Based on functional clustering, up- and down-regulated genes were mostly related to carbohydrate and lipid metabolism, enzyme activity and signal transduction. The expression of 20 selected clones involved with carbohydrate and lipid metabolism pathways was further studied by quantitative PCR. The data indicated that six clones similar to the genes ChREBP, FoxO1, apoB, IHPK2, KIF1B, and FSP27, which participate in de novo synthesis of fatty acid and secretion of very low density lipoproteins, had significantly lower expression levels in the hepatocytes treated with FFA mixtures. Meanwhile, 13 clones similar to the genes DGAT-1, ACSL1, DHRS7, PPARα, L-FABP, DGAT-2, PCK, ACSL3, CPT-1, A-FABP, PPARβ, MAT, and ALDOB had significantly higher expression levels in the hepatocytes treated with FFA mixtures. These results suggest that several metabolic pathways are altered in goose hepatocytes, which may be useful for further research into the molecular mechanism of goose hepatic steatosis.
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Affiliation(s)
- Zhixiong Pan
- Key Laboratory of Animal Genetic Resources, College of Animal Science and Technology, Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China
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Mauvoisin D, Mounier C. Hormonal and nutritional regulation of SCD1 gene expression. Biochimie 2011; 93:78-86. [DOI: 10.1016/j.biochi.2010.08.001] [Citation(s) in RCA: 158] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 07/16/2010] [Accepted: 08/03/2010] [Indexed: 01/08/2023]
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16
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Pickens MK, Ogata H, Soon RK, Grenert JP, Maher JJ. Dietary fructose exacerbates hepatocellular injury when incorporated into a methionine-choline-deficient diet. Liver Int 2010; 30:1229-39. [PMID: 20536716 PMCID: PMC3592570 DOI: 10.1111/j.1478-3231.2010.02285.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to model fatty liver disease in human beings. Recent studies have identified sucrose as a major contributor to MCD-related liver disease through its ability to promote hepatic de novo lipogenesis. AIMS To determine whether glucose and fructose, the two constitutents of sucrose, differ in their capacity to provoke steatohepatitis when incorporated individually into MCD formulas. MATERIALS & METHODS MCD and control formulas prepared with either glucose or fructose as the sole source of carbohydrate were fed to mice for 21 days. Liver injury was assessed biochemically and histologically together with hepatic gene expression and fatty acid analysis. RESULTS Mice fed MCD formulas developed similar degrees of hepatic steatosis whether they contained glucose or fructose. By contrast, mice fed MCD-fructose developed significantly more hepatocellular injury than mice fed MCD-glucose, judged by histology, apoptosis staining and serum alanine aminotransferase. Liver injury in MCD-fructose mice coincided with an exaggerated rise in the ratio of long-chain saturated to unsaturated fatty acids in the liver. Notably, hepatic inflammation was not enhanced in mice fed MCD-fructose, correlating instead with hepatic lipid peroxidation, which was equivalent in the two MCD groups. DISCUSSION Fructose is more cytotoxic than glucose when used as the source of carbohydrate in MCD formulas. CONCLUSION The data suggest the enhanced cytotoxicity of fructose in the MCD model is related to its ability to stimulate de novo lipogenesis, which yields harmful long-chain saturated fatty acids.
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Affiliation(s)
- Michael K. Pickens
- Department of Pediatrics, University of California, San Francisco, CA, USA,The Liver Center, University of California, San Francisco, CA, USA
| | - Hisanobu Ogata
- The Liver Center, University of California, San Francisco, CA, USA,Department of Internal Medicine, University of California, San Francisco, CA, USA
| | - Russell K. Soon
- The Liver Center, University of California, San Francisco, CA, USA,Department of Internal Medicine, University of California, San Francisco, CA, USA
| | - James P. Grenert
- The Liver Center, University of California, San Francisco, CA, USA,Department of Pathology, University of California, San Francisco, CA, USA
| | - Jacquelyn J. Maher
- The Liver Center, University of California, San Francisco, CA, USA,Department of Internal Medicine, University of California, San Francisco, CA, USA
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Shieh YS, Chang YS, Hong JR, Chen LJ, Jou LK, Hsu CC, Her GM. Increase of hepatic fat accumulation by liver specific expression of Hepatitis B virus X protein in zebrafish. Biochim Biophys Acta Mol Cell Biol Lipids 2010; 1801:721-30. [PMID: 20416398 DOI: 10.1016/j.bbalip.2010.04.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 03/25/2010] [Accepted: 04/12/2010] [Indexed: 02/06/2023]
Abstract
The pathogenesis of fatty liver disease remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis in zebrafish by liver specific expression of Hepatitis B virus X protein (HBx). Transgenic zebrafish lines, GBXs, which selectively express the GBx transgene (GFP-fused HBx gene) in liver, were established. GBX Liver phenotypes were evaluated by histopathology and molecular analysis of fatty acid (FA) metabolism-related genes expression. Most GBXs (66-81%) displayed obvious emaciation starting at 4 months old. Over 99% of the emaciated GBXs developed hepatic steatosis or steatohepatitis, which in turn led to liver hypoplasia. The liver histology of GBXs displayed steatosis, lobular inflammation, and balloon degeneration, similar to non-alcoholic steatohepatitis (NASH). Oil red O stain detected the accumulation of fatty droplets in GBXs. RT-PCR and Q-rt-PCR analysis revealed that GBx induced hepatic steatosis had significant increases in the expression of lipogenic genes, C/EBP-alpha, SREBP1, ChREBP and PPAR-gamma, which then activate key enzymes of the de novo FA synthesis, ACC1, FAS, SCD1, AGAPT, PAP and DGAT2. In addition, the steatohepatitic GBX liver progressed to liver degeneration and exhibited significant differential gene expression in apoptosis and stress. The GBX models exhibited both the genetic and functional factors involved in lipid accumulation and steatosis-associated liver injury. In addition, GBXs with transmissible NASH-like phenotypes provide a promising model for studying liver disease.
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Affiliation(s)
- Yun-Sheng Shieh
- Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
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18
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Levi M. The Kidney in Liver Disease. THE LIVER 2009:619-638. [DOI: 10.1002/9780470747919.ch40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Nascimento CMOD, Ribeiro EB, Oyama LM. Metabolism and secretory function of white adipose tissue: effect of dietary fat. AN ACAD BRAS CIENC 2009; 81:453-66. [DOI: 10.1590/s0001-37652009000300010] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 02/02/2009] [Indexed: 11/21/2022] Open
Abstract
Approximately 40% of the total energy consumed by western populations is represented by lipids, most of them being ingested as triacylglycerols and phospholipids. The focus of this review is to analyze the effect of the type of dietary fat on white adipose tissue metabolism and secretory function, particularly on haptoglobin, TNF-α, plasminogen activator inhibitor-1 and adiponectin secretion. Previous studies have demonstrated that the duration of the exposure to the high-fat feeding, amount of fatty acid present in the diet and the type of fatty acid may or may not have a significant effect on adipose tissue metabolism. However, the long-term or short-term high fat diets, especially rich in saturated fatty acids, probably by activation of toll-like receptors, stimulated the expression of proinflammatory adipokines and inhibited adiponectin expression. Further studies are needed to investigate the cellular mechanisms by which dietary fatty acids affect white adipose tissue metabolism and secretory functions.
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Flowers MT, Ntambi JM. Stearoyl-CoA desaturase and its relation to high-carbohydrate diets and obesity. BIOCHIMICA ET BIOPHYSICA ACTA 2009; 1791:85-91. [PMID: 19166967 PMCID: PMC2649790 DOI: 10.1016/j.bbalip.2008.12.011] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/10/2008] [Revised: 12/15/2008] [Accepted: 12/17/2008] [Indexed: 01/03/2023]
Abstract
Obesity is currently a worldwide epidemic and public health burden that increases the risk for developing insulin resistance and several chronic diseases such as diabetes, cardiovascular diseases and non-alcoholic fatty liver disease. The multifactorial causes of obesity include several genetic, dietary and lifestyle variables that together result in an imbalance between energy intake and energy expenditure. Dietary approaches to limit fat intake are commonly prescribed to achieve the hypocaloric conditions necessary for weight loss. But dietary fat restriction is often accompanied by increased carbohydrate intake, which can dramatically increase endogenous fatty acid synthesis depending upon carbohydrate composition. Since both dietary and endogenously synthesized fatty acids contribute to the whole-body fatty acid pool, obesity can therefore result from excessive fat or carbohydrate consumption. Stearoyl-Coenzyme A desaturase-1 (SCD1) is a delta-9 fatty acid desaturase that converts saturated fatty acids into monounsaturated fatty acids (MUFA) and this activity is elevated by dietary carbohydrate. Mice lacking Scd1 are protected from obesity and insulin resistance and are characterized by decreased fatty acid synthesis and increased fatty acid oxidation. In this review, we address the association of high-carbohydrate diets with increased SCD activity and summarize the current literature on the subject of SCD1 and body weight regulation.
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Affiliation(s)
- Matthew T. Flowers
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA
| | - James M. Ntambi
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA
- Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, USA
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