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Zhang Y, Ding R, Hu L, Liu E, Qu P. Epigenetics in metabolic dysfunction-associated steatohepatitis. Cell Signal 2025; 130:111684. [PMID: 39999913 DOI: 10.1016/j.cellsig.2025.111684] [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: 01/09/2025] [Revised: 02/16/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease involving genetics, environment, and lifestyle, with the potential to progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Although the pathogenesis of MASH is not fully clear, increasing evidence has indicated that epigenetics plays an important role in the genesis and progression of MASH, during which, as drastic changes in metabolites, epigenetics undergo drastic changes. Roles of chromatin structure, chromatin accessibility, DNA methylation, histone modification, and non-coding RNAs were considered as bridges of pathogenic factors and MASH. In this review, the research progress on the epigenetics of MASH was summarized, and indepth research and therapeutic strategies based on epigenetics is expected to bring new hope to MASH patients.
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Affiliation(s)
- Yanru Zhang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Ruike Ding
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
| | - Pengxiang Qu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
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Porter Starr KN, Connelly MA, Wallis J, North R, Zhang Q, Song K, González-Delgado JM, Brochu HN, Icenhour CR, Iyer LK, Miller MG, Huffman KM, Kraus WE, Bales CW. Effects of Blueberry Consumption on Fecal Microbiome Composition and Circulating Metabolites, Lipids, and Lipoproteins in a Randomized Controlled Trial of Older Adults with Overweight or Obesity: The BEACTIVE Trial. Nutrients 2025; 17:1200. [PMID: 40218958 PMCID: PMC11990464 DOI: 10.3390/nu17071200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Generous consumption of phytonutrient-rich foods, including blueberries, provides benefits to multiple physiologic and metabolic systems. This study explored the potential that regular, generous blueberry intake could favorably modulate fecal microbiome composition in sedentary older (>60 years) men and women with overweight or obesity (BMI ≥ 25 to 32 kg/m2). Methods: Participants (n = 55) were randomized to daily consumption of either lyophilized blueberry powder (equivalent to 1.5 cups of blueberries) or an indistinguishable placebo powder; both groups participated in weekly supervised exercise classes. Fecal samples were collected at 0 and 12 weeks and frozen. Following this, 16S rRNA gene sequencing was used to profile each participant's fecal microbiome. Blood biomarkers of cardiometabolic health were measured via nuclear magnetic resonance spectroscopy (NMR) pre- and post-treatment. Results: Comparing the baseline and endpoint results for the blueberry (n = 15) and placebo (n = 19) groups, there were no significant overall compositional differences or differences in the level of diversity in the fecal microbiome. However, in subjects whose diet included blueberry powder, there was a significant enrichment (p = 0.049) in the relative abundance of Coriobacteriales incertae sedis, a taxonomic group of bacteria that facilitates the metabolism of dietary polyphenols. The placebo group exhibited significant reductions in total cholesterol, LDL-C, non-HDL-C, total LDL-P, large LDL-P, and ApoB, while the blueberry group exhibited significant reductions in total HDL-P and ApoA-I after 12 weeks compared to baseline. Conclusions: Generous blueberry consumption may upregulate the ability of the older human gut to utilize dietary polyphenols by altering the fecal microbiome. Longer, larger-scale studies with blueberries or blueberry powder are needed to observe improvements in cardiometabolic risk factors in older adults with overweight or obesity.
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Affiliation(s)
- Kathryn N. Porter Starr
- Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27710, USA; (J.W.); (R.N.); (M.G.M.)
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; (K.M.H.); (W.E.K.); (C.W.B.)
- Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC 27710, USA
| | | | - Jessica Wallis
- Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27710, USA; (J.W.); (R.N.); (M.G.M.)
| | - Rebecca North
- Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27710, USA; (J.W.); (R.N.); (M.G.M.)
| | - Qimin Zhang
- Labcorp, Westborough, MA 01581, USA; (Q.Z.); (K.S.); (H.N.B.); (L.K.I.)
| | - Kuncheng Song
- Labcorp, Westborough, MA 01581, USA; (Q.Z.); (K.S.); (H.N.B.); (L.K.I.)
| | | | - Hayden N. Brochu
- Labcorp, Westborough, MA 01581, USA; (Q.Z.); (K.S.); (H.N.B.); (L.K.I.)
| | | | | | - Marshall G. Miller
- Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27710, USA; (J.W.); (R.N.); (M.G.M.)
| | - Kim M. Huffman
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; (K.M.H.); (W.E.K.); (C.W.B.)
- Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - William E. Kraus
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; (K.M.H.); (W.E.K.); (C.W.B.)
- Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Connie W. Bales
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; (K.M.H.); (W.E.K.); (C.W.B.)
- Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC 27710, USA
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Perumal SK, Arumugam MK, Osna NA, Rasineni K, Kharbanda KK. Betaine regulates the gut-liver axis: a therapeutic approach for chronic liver diseases. Front Nutr 2025; 12:1478542. [PMID: 40196019 PMCID: PMC11973089 DOI: 10.3389/fnut.2025.1478542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Chronic liver disease is defined by persistent harm to the liver that might result in decreased liver function. The two prevalent chronic liver diseases are alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). There is ample evidence that the pathogenesis of these two chronic liver diseases is closely linked to gastrointestinal dysfunctions that alters the gut-liver crosstalk. These alterations are mediated through the imbalances in the gut microbiota composition/function that combined with disruption in the gut barrier integrity allows for harmful gut microbes and their toxins to enter the portal circulation and reach the liver to elicit an inflammatory response. This leads to further recruitment of systemic inflammatory cells, such as neutrophils, T-cells, and monocytes into the liver, which perpetuate additional inflammation and the development of progressive liver damage. Many therapeutic modalities, currently used to prevent, attenuate, or treat chronic liver diseases are aimed at modulating gut dysbiosis and improving intestinal barrier function. Betaine is a choline-derived metabolite and a methyl group donor with antioxidant, anti-inflammatory and osmoprotectant properties. Studies have shown that low betaine levels are associated with higher levels of organ damage. There have been several publications demonstrating the role of betaine supplementation in preventing the development of ALD and MASLD. This review explores the protective effects of betaine through its role as a methyl donor and its capacity to regulate the protective gut microbiota and maintain intestinal barrier integrity to prevent the development of these chronic liver diseases. Further studies are needed to enhance our understanding of its therapeutic potential that could pave the way for targeted interventions in the management of not only chronic liver diseases, but other inflammatory bowel diseases or systemic inflammatory conditions.
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Affiliation(s)
- Sathish Kumar Perumal
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Madan Kumar Arumugam
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Tan EY, Muthiah MD, Sanyal AJ. Metabolomics at the cutting edge of risk prediction of MASLD. Cell Rep Med 2024; 5:101853. [PMID: 39657668 PMCID: PMC11722125 DOI: 10.1016/j.xcrm.2024.101853] [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: 07/25/2024] [Revised: 10/12/2024] [Accepted: 11/14/2024] [Indexed: 12/12/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health threat globally. Management of patients afflicted with MASLD and research in this domain are limited by the lack of robust well-established non-invasive biomarkers for diagnosis, prognostication, and monitoring. The circulating metabolome reflects both the systemic metabo-inflammatory milieu and changes in the liver in affected individuals. In this review we summarize the available literature on changes in the different components of the metabolome in MASLD with a focus on changes that are linked to the presence of underlying steatohepatitis, severity of disease activity, and fibrosis stage. We further summarize the existing literature around biomarker panels that are derived from interrogation of the metabolome. Their relevance to disease biology and utility in practice are also discussed. We further highlight potential direction for future studies particularly to ensure they are fit for purpose and suitable for widespread use.
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Affiliation(s)
- En Ying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Mercado-Gómez M, Goikoetxea-Usandizaga N, Kerbert AJC, Gracianteparaluceta LU, Serrano-Maciá M, Lachiondo-Ortega S, Rodriguez-Agudo R, Gil-Pitarch C, Simón J, González-Recio I, Fondevila MF, Santamarina-Ojeda P, Fraga MF, Nogueiras R, Heras JDL, Jalan R, Martínez-Chantar ML, Delgado TC. The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis. Metabolism 2024; 158:155952. [PMID: 38906371 DOI: 10.1016/j.metabol.2024.155952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/30/2024] [Accepted: 06/07/2024] [Indexed: 06/23/2024]
Abstract
INTRODUCTION Ammonia is a pathogenic factor implicated in the progression of metabolic-associated steatotic liver disease (MASLD). The contribution of the glutaminase 1 (GLS) isoform, an enzyme converting glutamine to glutamate and ammonia, to hepatic ammonia build-up and the mechanisms underlying its upregulation in metabolic-associated steatohepatitis (MASH) remain elusive. METHODS Multiplex transcriptomics and targeted metabolomics analysis of liver biopsies in dietary mouse models representing the whole spectra of MASLD were carried out to characterize the relevance of hepatic GLS during disease pathological progression. In addition, the acute effect of liver-specific GLS inhibition in hepatic ammonia content was evaluated in cultured hepatocytes and in in vivo mouse models of diet-induced MASLD. Finally, the regulatory mechanisms of hepatic GLS overexpression related to the lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4) axis were explored in the context of MASH. RESULTS In mouse models of diet-induced MASLD, we found that augmented liver GLS expression is closely associated with the build-up of hepatic ammonia as the disease progresses from steatosis to steatohepatitis. Importantly, the acute silencing/pharmacological inhibition of GLS diminishes the ammonia burden in cultured primary mouse hepatocytes undergoing dedifferentiation, in steatotic hepatocytes, and in a mouse model of diet-induced steatohepatitis, irrespective of changes in ureagenesis and gut permeability. Under these conditions, GLS upregulation in the liver correlates positively with the hepatic expression of TLR4 that recognizes LPS. In agreement, the pharmacological inhibition of TLR4 reduces GLS and hepatic ammonia content in LPS-stimulated mouse hepatocytes and hyperammonemia animal models of endotoxemia. CONCLUSIONS Overall, our results suggest that the LPS/TLR4 axis regulates hepatic GLS expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.
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Affiliation(s)
- Maria Mercado-Gómez
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | | | - Marina Serrano-Maciá
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Sofia Lachiondo-Ortega
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Rubén Rodriguez-Agudo
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Clàudia Gil-Pitarch
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Jorge Simón
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Irene González-Recio
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Marcos F Fondevila
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
| | - Pablo Santamarina-Ojeda
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Asturias, Spain; Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029 Madrid, Spain; Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940 El Entrego, Asturias, Spain
| | - Mario F Fraga
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Asturias, Spain; Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029 Madrid, Spain; Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940 El Entrego, Asturias, Spain; Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006 Oviedo, Asturias, Spain
| | - Rubén Nogueiras
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 28029 Madrid, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
| | - Javier de Las Heras
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; Division of Paediatric Metabolism, CIBERER, MetabERN, Cruces University Hospital, 48903 Barakaldo, Spain.; Department of Paediatrics, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - María Luz Martínez-Chantar
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain.
| | - Teresa C Delgado
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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Sevilla-González M, Garibay-Gutiérrez MF, Vargas-Vázquez A, Medina-García AC, Ordoñez-Sánchez ML, Clish CB, Almeda-Valdes P, Tusie-Luna T. Metabolomic Profile Alterations Associated with the SLC16A11 Risk Haplotype Following a Lifestyle Intervention in People With Prediabetes. Curr Dev Nutr 2024; 8:104444. [PMID: 39310668 PMCID: PMC11416210 DOI: 10.1016/j.cdnut.2024.104444] [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: 05/27/2024] [Revised: 08/11/2024] [Accepted: 08/15/2024] [Indexed: 09/25/2024] Open
Abstract
Background A risk haplotype in SLC16A11 characterized by alterations in fatty acid metabolism emerged as a genetic risk factor associated with increased susceptibility to type 2 diabetes (T2D) in Mexican population. Its role on treatment responses is not well understood. Objectives We aimed to determine the impact of the risk haplotype on the metabolomic profile during a lifestyle intervention (LSI). Methods We recruited Mexican-mestizo individuals with ≥1 prediabetes criteria according to the American Diabetes Association with a body mass index between 25 and 45 kg/m2. We conducted a 24-wk quasiexperimental LSI study for diabetes prevention. Here, we compared longitudinal plasma liquid chromatography/mass spectrometry metabolomic changes between carriers and noncarriers. We analyzed the association of risk haplotype with metabolites leveraging repeated assessments using multivariable-adjusted linear mixed models. Results Before the intervention, carriers (N = 21) showed higher concentrations of hippurate, C16 carnitine, glycine, and cinnamoylglycine. After 24 wk of LSI, carriers exhibited a deleterious metabolomic profile. This profile was characterized by increased concentrations of hippurate, cinnamoglycine, xanthosine, N-acetylputrescine, L-acetylcarnitine, ceramide (d18:1/24:1), and decreased concentrations of citrulline and phosphatidylethanolamine. These metabolites were associated with higher concentrations of total cholesterol, triglycerides, and low density lipoprotein cholesterol. The effect of LSI on the risk haplotype was notably more pronounced in its impact on 2 metabolites: methylmalonylcarnitine (β: -0.56; P-interaction = 0.014) and betaine (β: -0.64; P-interaction = 0.017). Interestingly, lower consumption across visits of polyunsaturated (β: -0.038; P = 0.017) fatty acids were associated with higher concentrations of methylmalonylcarnitine. Covariates for adjustment across models included age, sex, genetic ancestry principal components, and body mass index. Conclusions Our study highlights the persistence of deleterious metabolomic patterns associated with the risk haplotype before and during a 24-wk LSI. We also emphasize the potential regulatory role of polyunsaturated fatty acids on methylmalonylcarnitine concentrations suggesting a route for improving interventions for individuals with high-genetic risk.
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Affiliation(s)
- Magdalena Sevilla-González
- Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Maria Fernanda Garibay-Gutiérrez
- Unidad de Investigacion en Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran,” Mexico City, Mexico
- Departamento de Fisiología. Escuela Nacional de Ciencias Biológicas, Instituto Politecnico Nacional, Mexico City, Mexico
| | - Arsenio Vargas-Vázquez
- Unidad de Investigacion en Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran,” Mexico City, Mexico
| | - Andrea Celeste Medina-García
- Unidad de Biologia Molecular y Medicina Genomica, Insituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
- Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Maria Luisa Ordoñez-Sánchez
- Unidad de Biologia Molecular y Medicina Genomica, Insituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Clary B Clish
- Metabolomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Paloma Almeda-Valdes
- Unidad de Investigacion en Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran,” Mexico City, Mexico
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Teresa Tusie-Luna
- Unidad de Biologia Molecular y Medicina Genomica, Insituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
- Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
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Kathirvel E, Morgan K, Malysheva OV, Caudill MA, Morgan TR. Betaine for the prevention and treatment of insulin resistance and fatty liver in a high-fat dietary model of insulin resistance in C57BL mice. Front Nutr 2024; 11:1409972. [PMID: 39119463 PMCID: PMC11307150 DOI: 10.3389/fnut.2024.1409972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
Aim The aim was to investigate mechanisms by which betaine improves hepatic insulin signaling in a dietary mouse model of insulin resistance and fatty liver. Methods C57BL 6J mice were fed a standard diet (SF), a standard diet with betaine (SFB), a nutritionally complete high fat (HF) diet, or a high fat diet with betaine (HFB) for 14 weeks. In a separate experiment, mice were fed high fat diet for 18 weeks, half of whom received betaine for the final 4 weeks. Activation of insulin signaling in the liver was assessed by western blot. Insulin signaling was also assessed in insulin resistant primary human hepatocytes treated with betaine. Results As compared with SF, mice receiving HF diet were heavier, had more hepatic steatosis, and abnormal glucose tolerance test (GTT). Betaine content in liver and serum was 50% lower in HF than in SF; betaine supplementation restored serum and liver betaine content. Betaine treatment of HF reduced whole body insulin resistance as measured by GTT. Betaine treatment of HF increased tyrosine phosphorylation of insulin receptor substrate-1 and phosphorylation (activation) of Akt, and increased hepatic glycogen content. In vitro, betaine reversed insulin resistance in primary human hepatocytes by increasing insulin-stimulated tyrosine phosphorylation of IRS1 and of Akt. Conclusion Betaine supplementation reduced whole body insulin resistance and increased activation of insulin signaling pathways in the liver in a mouse model of insulin resistance and fatty liver created by feeding a nutritionally complete high fat diet for 14 weeks. Betaine also reduced liver injury as assessed by ALT and by liver histology. In vitro, betaine reversed insulin resistance by increasing insulin-stimulated tyrosine phosphorylation of IRS1 and activation of downstream proteins in the insulin signaling cascade in insulin resistant primary human hepatocytes.
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Affiliation(s)
- Elango Kathirvel
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
| | - Kengathevy Morgan
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
| | - Olga V. Malysheva
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
| | - Marie A. Caudill
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
| | - Timothy R. Morgan
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
- Department of Medicine, University of California, Irvine, Irvine, CA, United States
- Medical Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
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Pirola CJ, Sookoian S. Drug repurposing in MASLD and MASH-cirrhosis: Targets and treatment approaches based on pathways analysis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 207:193-206. [PMID: 38942537 DOI: 10.1016/bs.pmbts.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Designing and predicting novel drug targets to accelerate drug discovery for treating metabolic dysfunction-associated steatohepatitis (MASH)-cirrhosis is a challenging task. The presence of superimposed (nested) and co-occurring clinical and histological phenotypes, namely MASH and cirrhosis, may partly explain this. Thus, in this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Here, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of MASH-cirrhosis. Our findings indicate that the pathogenesis of MASH-cirrhosis can be explained by perturbations in multiple, simultaneous, and overlapping molecular processes. In this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Therefore, we used systems biology modeling to provide evidence that MASH and cirrhosis paradoxically present unique and distinct as well as common disease mechanisms, including a network of molecular targets. More importantly, pathway analysis revealed straightforward results consistent with modulation of the immune response, cell cycle control, and epigenetic regulation. In conclusion, the selection of potential therapies for MASH-cirrhosis should be guided by a better understanding of the underlying biological processes and molecular perturbations that progressively damage liver tissue and its underlying structure. Therapeutic options for patients with MASH may not necessarily be of choice for MASH cirrhosis. Therefore, the biology of the disease and the processes associated with its natural history must be at the forefront of the decision-making process.
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Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Investigación Traslacional en Salud, Universidad Maimónides, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
| | - Silvia Sookoian
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Clinical and Molecular Hepatology, Centro de Investigación Traslacional en Salud, Universidad Maimónides, Buenos Aires, Argentina; Facultad de Ciencias de la Salud, Universidad Maimónides, Buenos Aires, Argentina.
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Ding X, He X, Tang B, Lan T. Integrated traditional Chinese and Western medicine in the prevention and treatment of non-alcoholic fatty liver disease: future directions and strategies. Chin Med 2024; 19:21. [PMID: 38310315 PMCID: PMC10838467 DOI: 10.1186/s13020-024-00894-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/23/2024] [Indexed: 02/05/2024] Open
Abstract
Traditional Chinese medicine (TCM) has been widely used for several centuries for metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). At present, NAFLD has become the most prevalent form of chronic liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. However, there is still a lack of effective treatment strategies in Western medicine. The development of NAFLD is driven by multiple mechanisms, including genetic factors, insulin resistance, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, gut microbiota dysbiosis, and adipose tissue dysfunction. Currently, certain drugs, including insulin sensitizers, statins, vitamin E, ursodeoxycholic acid and betaine, are proven to be beneficial for the clinical treatment of NAFLD. Due to its complex pathogenesis, personalized medicine that integrates various mechanisms may provide better benefits to patients with NAFLD. The holistic view and syndrome differentiation of TCM have advantages in treating NAFLD, which are similar to the principles of personalized medicine. In TCM, NAFLD is primarily classified into five types based on clinical experience. It is located in the liver and is closely related to spleen and kidney functions. However, due to the multi-component characteristics of traditional Chinese medicine, its application in the treatment of NAFLD has been considerably limited. In this review, we summarize the advances in the pathogenesis and treatment of NAFLD, drawn from both the Western medicine and TCM perspectives. We highlight that Chinese and Western medicine have complementary advantages and should receive increased attention in the prevention and treatment of NAFLD.
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Affiliation(s)
- Xin Ding
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Xu He
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Bulang Tang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
- School of Pharmacy, Harbin Medical University, Harbin, 150086, China.
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10
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Tobias DK, Hamaya R, Clish CB, Liang L, Deik A, Dennis C, Bullock K, Zhang C, Hu FB, Manson JE. Type 2 diabetes metabolomics score and risk of progression to type 2 diabetes among women with a history of gestational diabetes mellitus. Diabetes Metab Res Rev 2024; 40:e3763. [PMID: 38287718 PMCID: PMC10842268 DOI: 10.1002/dmrr.3763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/08/2023] [Accepted: 11/05/2023] [Indexed: 01/31/2024]
Abstract
BACKGROUND Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D-metabolite pattern with a risk of progression to T2D among high-risk women with a history of gestational diabetes mellitus (GDM). METHODS The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age-matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1-5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. RESULTS The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20-fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend<0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p < 0.0001). CONCLUSIONS A pattern of plasma metabolites among high-risk women is associated with a markedly elevated risk of progression to T2D later in life.
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Affiliation(s)
- Deirdre K. Tobias
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Nutrition Department, Harvard TH Chan School of Public Health, Boston, MA
| | - Rikuta Hamaya
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
| | | | - Liming Liang
- Biostatistics Department, Harvard TH Chan School of Public Health, Boston, MA
| | - Amy Deik
- Broad Institute of MIT and Harvard, Cambridge, MA
| | | | | | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Frank B. Hu
- Nutrition Department, Harvard TH Chan School of Public Health, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - JoAnn E. Manson
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
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11
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Dongoran RA, Tu FC, Liu CH. Current insights into the interplay between gut microbiota-derived metabolites and metabolic-associated fatty liver disease. Tzu Chi Med J 2023; 35:290-299. [PMID: 38035056 PMCID: PMC10683522 DOI: 10.4103/tcmj.tcmj_122_23] [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: 05/11/2023] [Revised: 05/29/2023] [Accepted: 07/11/2023] [Indexed: 12/02/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent and challenging disease associated with a significant health and economic burden. MAFLD has been subjected to and widely investigated in many studies; however, the underlying pathogenesis and its progression have yet to understand fully. Furthermore, precise biomarkers for diagnosing and specific drugs for treatment are yet to be discovered. Increasing evidence has proven gut microbiota as the neglected endocrine organ that regulates homeostasis and immune response. Targeting gut microbiota is an essential strategy for metabolic diseases, including MAFLD. Gut microbiota in the gut-liver axis is connected through tight bidirectional links through the biliary tract, portal vein, and systemic circulation, producing gut microbiota metabolites. This review focuses on the specific correlation between gut microbiota metabolites and MAFLD. Gut microbiota metabolites are biologically active in the host and, through subsequent changes and biological activities, provide implications for MAFLD. Based on the review studies, gut-liver axis related-metabolites including short-chain fatty acids, bile acids (BAs), lipopolysaccharide, choline and its metabolites, indole and its derivates, branched-chain amino acids, and methionine cycle derivates was associated with MAFLD and could be promising MAFLD diagnosis biomarkers, as well as the targets for MAFLD new drug discovery.
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Affiliation(s)
- Rachmad Anres Dongoran
- Indonesian Food and Drug Authority, Jakarta, Indonesia
- Center for Chinese Studies, National Central Library, Taipei, Taiwan
- Program in Asia Pacific Regional Studies, Department of Taiwan and Regional Studies, College of Humanities and Social Sciences, National Dong Hwa University, Hualien, Taiwan
| | - Fang-Cen Tu
- Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chin-Hung Liu
- Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of Pharmacology, School of Medicine, Tzu Chi University, Hualien, Taiwan
- Graduate Institute of Clinical Pharmacy, School of Medicine, Tzu Chi University, Hualien, Taiwan
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12
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Luo L, Chang Y, Sheng L. Gut-liver axis in the progression of nonalcoholic fatty liver disease: From the microbial derivatives-centered perspective. Life Sci 2023; 321:121614. [PMID: 36965522 DOI: 10.1016/j.lfs.2023.121614] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/16/2023] [Accepted: 03/18/2023] [Indexed: 03/27/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the world's most common chronic liver diseases. However, its pathogenesis remains unclear. With the deepening of research, NAFLD is considered a metabolic syndrome associated with the environment, heredity, and metabolic disorders. Recently, the close relationship between the intestinal microbiome and NAFLD has been discovered, and the theory of the "gut-liver axis" has been proposed. In short, the gut bacteria directly reach the liver via the portal vein through the damaged intestinal wall or indirectly participate in the development of NAFLD through signaling pathways mediated by their components and metabolites. This review focuses on the roles of microbiota-derived lipopolysaccharide, DNA, peptidoglycan, bile acids, short-chain fatty acids, endogenous ethanol, choline and its metabolites, indole and its derivatives, and bilirubin and its metabolites in the progression of NAFLD, which may provide significative insights into the pathogenesis, diagnosis, and treatment for this highly prevalent liver disease.
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Affiliation(s)
- Lijun Luo
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Yongchun Chang
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Li Sheng
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
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13
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Gong M, Lu H, Li L, Feng M, Zou Z. Integration of transcriptomics and metabonomics revealed the protective effects of hemp seed oil against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in mice. Food Funct 2023; 14:2096-2111. [PMID: 36734470 DOI: 10.1039/d2fo03054c] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with few therapeutic options available currently. Hemp seed oil extracted from the seeds of hemp (Cannabis sativa L.) has significant nutritional and biological properties due to the unique composition of polyunsaturated fatty acids and various antioxidant compounds. However, little is known about the beneficial effects and molecular mechanisms of hemp seed oil on NASH. Here, the hepatoprotective effects of hemp seed oil on methionine-choline-deficient (MCD) diet-induced NASH in C57BL/6 mice were explored via integration of transcriptomics and metabolomics. Hemp seed oil could improve hepatic steatosis, inflammation and fibrosis in mice with MCD diet-induced NASH. In a nuclear magnetic resonance (NMR)-based metabonomic study, the hepatic and urinary metabolic profiles of mice supplemented with hemp seed oil showed a tendency to recover to healthy controls compared to those of NASH mice. Eight potential biomarkers associated with NASH in both liver tissue and urine were restored to near normal levels by administration of hemp seed oil. The proposed pathways were mainly involved in pyrimidine metabolism, one-carbon metabolism, amino acid metabolism, glycolysis and the tricarboxylic acid (TCA) cycle. Hepatic transcriptomics based on Illumina RNA-Seq sequencing showed that hemp seed oil exerted anti-NASH activities by regulating multiple signaling pathways, e.g., downregulation of the TNF signaling pathway, the IL-17 signaling pathway, the MAPK signaling pathway and the NF-κB signaling pathway, which played a pivotal role in the pathogenesis of NASH. In particular, integration of metabonomic and transcriptomic results suggested that hemp seed oil could attenuate NASH-related liver fibrosis by inhibition of glutaminolysis. These results provided new insights into the hepatoprotective effects of hemp seed oil against MCD diet-induced NASH and hemp seed oil might have potential as an effective therapy for NASH.
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Affiliation(s)
- Mengjuan Gong
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Hailong Lu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Lixi Li
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Meiqi Feng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhongjie Zou
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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14
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van den Berg EH, Flores-Guerrero JL, Garcia E, Connelly MA, de Meijer VE, Bakker SJL, Blokzijl H, Dullaart RPF. High plasma levels of betaine, a trimethylamine N-Oxide-related metabolite, are associated with the severity of cirrhosis. Liver Int 2023; 43:424-433. [PMID: 35585781 PMCID: PMC10084422 DOI: 10.1111/liv.15310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/09/2022] [Accepted: 05/16/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity. METHODS Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score. RESULTS Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively). CONCLUSION Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation.
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Affiliation(s)
- Eline H van den Berg
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jose L Flores-Guerrero
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Erwin Garcia
- Laboratory Corporation of America Holdings (Labcorp), Morrisville, North Carolina, USA
| | - Margery A Connelly
- Laboratory Corporation of America Holdings (Labcorp), Morrisville, North Carolina, USA
| | - Vincent E de Meijer
- Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | | | - Stephan J L Bakker
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robin P F Dullaart
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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15
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Ilyas A, Wijayasinghe YS, Khan I, El Samaloty NM, Adnan M, Dar TA, Poddar NK, Singh LR, Sharma H, Khan S. Implications of trimethylamine N-oxide (TMAO) and Betaine in Human Health: Beyond Being Osmoprotective Compounds. Front Mol Biosci 2022; 9:964624. [PMID: 36310589 PMCID: PMC9601739 DOI: 10.3389/fmolb.2022.964624] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Osmolytes are naturally occurring small molecular weight organic molecules, which are accumulated in large amounts in all life forms to maintain the stability of cellular proteins and hence preserve their functions during adverse environmental conditions. Trimethylamine N-oxide (TMAO) and N,N,N-trimethylglycine (betaine) are methylamine osmolytes that have been extensively studied for their diverse roles in humans and have demonstrated opposing relations with human health. These osmolytes are obtained from food and synthesized endogenously using dietary constituents like choline and carnitine. Especially, gut microbiota plays a vital role in TMAO synthesis and contributes significantly to plasma TMAO levels. The elevated plasma TMAO has been reported to be correlated with the pathogenesis of numerous human diseases, including cardiovascular disease, heart failure, kidney diseases, metabolic syndrome, etc.; Hence, TMAO has been recognized as a novel biomarker for the detection/prediction of several human diseases. In contrast, betaine acts as a methyl donor in one-carbon metabolism, maintains cellular S-adenosylmethionine levels, and protects the cells from the harmful effects of increased plasma homocysteine. Betaine also demonstrates antioxidant and anti-inflammatory activities and has a promising therapeutic value in several human diseases, including homocystinuria and fatty liver disease. The present review examines the multifarious functions of TMAO and betaine with possible molecular mechanisms towards a better understanding of their emerging and diverging functions with probable implications in the prevention, diagnosis, and treatment of human diseases.
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Affiliation(s)
- Ashal Ilyas
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Yasanandana Supunsiri Wijayasinghe
- Department of Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
| | - Ilyas Khan
- Department of Mathematics, College of Science Al-Zulfi, Majmaah University, Al-Majmaah, Saudi Arabia
| | - Nourhan M. El Samaloty
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Tanveer Ali Dar
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Nitesh Kumar Poddar
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan, India,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
| | - Laishram R. Singh
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Hemlata Sharma
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan, India
| | - Shahanavaj Khan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia,Department of Medical Lab Technology, Indian Institute of Health and Technology (IIHT), Saharanpur, Uttar Pradesh, India,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
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16
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Huang Q, Xin X, Sun Q, An Z, Gou X, Feng Q. Plant-derived bioactive compounds regulate the NLRP3 inflammasome to treat NAFLD. Front Pharmacol 2022; 13:896899. [PMID: 36016562 PMCID: PMC9396216 DOI: 10.3389/fphar.2022.896899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/29/2022] [Indexed: 11/29/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by abnormal accumulation of hepatic fat and inflammatory response with complex pathogenesis. Over activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome triggers the secretion of interleukin (IL)-1β and IL-18, induces pyroptosis, and promotes the release of a large number of pro-inflammatory proteins. All of which contribute to the development of NAFLD. There is a great deal of evidence indicating that plant-derived active ingredients are effective and safe for NAFLD management. This review aims to summarize the research progress of 31 active plant-derived components (terpenoids, flavonoids, alkaloids, and phenols) that alleviate lipid deposition, inflammation, and pyroptosis by acting on the NLRP3 inflammasome studied in both in vitro and in vivo NAFLD models. These studies confirmed that the NLRP3 inflammasome and its related genes play a key role in NAFLD amelioration, providing a starting point for further study on the correlation of plant-derived compounds treatment with the NLRP3 inflammasome and NAFLD.
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Affiliation(s)
- Qian Huang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Xin
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - QinMei Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziming An
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai, China
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
- *Correspondence: Qin Feng,
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17
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Plasma Metabolomics and Machine Learning-Driven Novel Diagnostic Signature for Non-Alcoholic Steatohepatitis. Biomedicines 2022; 10:biomedicines10071669. [PMID: 35884973 PMCID: PMC9312563 DOI: 10.3390/biomedicines10071669] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/16/2022] Open
Abstract
We performed targeted metabolomics with machine learning (ML)-based interpretation to identify metabolites that distinguish the progression of nonalcoholic fatty liver disease (NAFLD) in a cohort. Plasma metabolomics analysis was conducted in healthy control subjects (n = 25) and patients with NAFL (n = 42) and nonalcoholic steatohepatitis (NASH, n = 19) by gas chromatography-tandem mass spectrometry (MS/MS) and liquid chromatography-MS/MS as well as RNA sequencing (RNA-seq) analyses on liver tissues from patients with varying stages of NAFLD (n = 12). The resulting metabolomic data were subjected to routine statistical and ML-based analyses and multi-omics interpretation with RNA-seq data. We found 6 metabolites that were significantly altered in NAFLD among 79 detected metabolites. Random-forest and multinomial logistic regression analyses showed that eight metabolites (glutamic acid, cis-aconitic acid, aspartic acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, myristoleic acid, and tyrosine) could distinguish the three groups. Then, the recursive partitioning and regression tree algorithm selected three metabolites (glutamic acid, isocitric acid, and aspartic acid) from these eight metabolites. With these three metabolites, we formulated an equation, the MetaNASH score that distinguished NASH with excellent performance. In addition, metabolic map construction and correlation assays integrating metabolomics data into the transcriptome datasets of the liver showed correlations between the concentration of plasma metabolites and the expression of enzymes governing metabolism and specific alterations of these correlations in NASH. Therefore, these findings will be useful for evaluation of altered metabolism in NASH and understanding of pathophysiologic implications from metabolite profiles in relation to NAFLD progression.
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18
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Abstract
Introduction: Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.Areas covered: By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.Expert opinion: Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.
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Affiliation(s)
- Carlos Jose Pirola
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (Conicet)-university of Buenos Aires. Institute of Medical Research (IDIM)
| | - Silvia Sookoian
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires. Institute of Medical Research (IDIM), Buenos Aires, Argentina
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19
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Wang H, Wu Y, Tang W. Methionine cycle in nonalcoholic fatty liver disease and its potential applications. Biochem Pharmacol 2022; 200:115033. [PMID: 35395242 DOI: 10.1016/j.bcp.2022.115033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/31/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
As a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.
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Affiliation(s)
- Haoyu Wang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Yanwei Wu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Wei Tang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
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20
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Masoodi M, Gastaldelli A, Hyötyläinen T, Arretxe E, Alonso C, Gaggini M, Brosnan J, Anstee QM, Millet O, Ortiz P, Mato JM, Dufour JF, Orešič M. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat Rev Gastroenterol Hepatol 2021; 18:835-856. [PMID: 34508238 DOI: 10.1038/s41575-021-00502-9] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
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Affiliation(s)
- Mojgan Masoodi
- Institute of Clinical Chemistry, Bern University Hospital, Bern, Switzerland.
| | | | - Tuulia Hyötyläinen
- School of Natural Sciences and Technology, Örebro University, Örebro, Sweden
| | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | | | | | | | - Quentin M Anstee
- Clinical & Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Oscar Millet
- Precision Medicine & Metabolism, CIC bioGUNE, CIBERehd, BRTA, Bizkaia Technology Park, Derio, Spain
| | - Pablo Ortiz
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - Jose M Mato
- Precision Medicine & Metabolism, CIC bioGUNE, CIBERehd, BRTA, Bizkaia Technology Park, Derio, Spain
| | - Jean-Francois Dufour
- University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.,Hepatology, Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - Matej Orešič
- School of Medical Sciences, Örebro University, Örebro, Sweden. .,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
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21
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Robinson EJ, Taddeo MC, Chu X, Shi W, Wood C, Still C, Rovnyak VG, Rovnyak D. Aqueous Metabolite Trends for the Progression of Nonalcoholic Fatty Liver Disease in Female Bariatric Surgery Patients by Targeted 1H-NMR Metabolomics. Metabolites 2021; 11:metabo11110737. [PMID: 34822395 PMCID: PMC8619318 DOI: 10.3390/metabo11110737] [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: 09/12/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 01/14/2023] Open
Abstract
Determining biomarkers and better characterizing the biochemical progression of nonalcoholic fatty liver disease (NAFLD) remains a clinical challenge. A targeted 1H-NMR study of serum, combined with clinical variables, detected and localized biomarkers to stages of NAFLD in morbidly obese females. Pre-surgery serum samples from 100 middle-aged, morbidly obese female subjects, grouped on gold-standard liver wedge biopsies (non-NAFLD; steatosis; and fibrosis) were collected, extracted, and analyzed in aqueous (D2O) buffer (1H, 600 MHz). Profiled concentrations were subjected to exploratory statistical analysis. Metabolites varying significantly between the non-NAFLD and steatosis groups included the ketone bodies 3-hydroxybutyrate (↓; p = 0.035) and acetone (↓; p = 0.012), and also alanine (↑; p = 0.004) and a putative pyruvate signal (↑; p = 0.003). In contrast, the steatosis and fibrosis groups were characterized by 2-hydroxyisovalerate (↑; p = 0.023), betaine (↓; p = 0.008), hypoxanthine (↓; p = 0.003), taurine (↓; p = 0.001), 2-hydroxybutyrate (↑; p = 0.045), 3-hydroxyisobutyrate (↑; p = 0.046), and increasing medium chain fatty acids. Exploratory classification models with and without clinical variables exhibited overall success rates ca. 75–85%. In the study conditions, inhibition of fatty acid oxidation and disruption of the hepatic urea cycle are supported as early features of NAFLD that continue in fibrosis. In fibrosis, markers support inflammation, hepatocyte damage, and decreased liver function. Complementarity of NMR concentrations and clinical information in classification models is shown. A broader hypothesis that standard-of-care sera can yield metabolomic information is supported.
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Affiliation(s)
- Emma J. Robinson
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
| | - Matthew C. Taddeo
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
| | - Xin Chu
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Weixing Shi
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Craig Wood
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Christopher Still
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | | | - David Rovnyak
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
- Correspondence:
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22
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Arumugam MK, Paal MC, Donohue TM, Ganesan M, Osna NA, Kharbanda KK. Beneficial Effects of Betaine: A Comprehensive Review. BIOLOGY 2021; 10:456. [PMID: 34067313 PMCID: PMC8224793 DOI: 10.3390/biology10060456] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/06/2021] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
Medicinal herbs and many food ingredients possess favorable biological properties that contribute to their therapeutic activities. One such natural product is betaine, a stable, nontoxic natural substance that is present in animals, plants, and microorganisms. Betaine is also endogenously synthesized through the metabolism of choline or exogenously consumed through dietary intake. Betaine mainly functions as (i) an osmolyte and (ii) a methyl-group donor. This review describes the major physiological effects of betaine in whole-body health and its ability to protect against both liver- as well as non-liver-related diseases and conditions. Betaine's role in preventing/attenuating both alcohol-induced and metabolic-associated liver diseases has been well studied and is extensively reviewed here. Several studies show that betaine protects against the development of alcohol-induced hepatic steatosis, apoptosis, and accumulation of damaged proteins. Additionally, it can significantly prevent/attenuate progressive liver injury by preserving gut integrity and adipose function. The protective effects are primarily associated with the regulation of methionine metabolism through removing homocysteine and maintaining cellular SAM:SAH ratios. Similarly, betaine prevents metabolic-associated fatty liver disease and its progression. In addition, betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development. To conclude, betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Matthew C. Paal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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23
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Abstract
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) poses a growing challenge in terms of its prevention and treatment. The 'multiple hits' hypothesis of multiple insults, such as dietary fat intake, de novo lipogenesis, insulin resistance, oxidative stress, mitochondrial dysfunction, gut dysbiosis and hepatic inflammation, can provide a more accurate explanation of the pathogenesis of NAFLD. Betaine plays important roles in regulating the genes associated with NAFLD through anti-inflammatory effects, increased free fatty oxidation, anti-lipogenic effects and improved insulin resistance and mitochondrial function; however, the mechanism of betaine remains elusive.
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24
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Gong MJ, Zhu CY, Zou ZJ, Han B, Huang P. Therapeutic potential of puerarin against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis determined by combination of 1H NMR spectroscopy-based metabonomics and 16S rRNA gene sequencing. J Pharm Biomed Anal 2021; 197:113964. [PMID: 33601157 DOI: 10.1016/j.jpba.2021.113964] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022]
Abstract
Previously published studies have revealed the protective effect of puerarin against non-alcoholic steatohepatitis (NASH), but the definite mechanism of this effect still remains unclear. The present work was an attempt to assess the beneficial effects and the underlying mechanisms of puerarin on methionine-choline-deficient (MCD) diet-induced NASH in C57BL/6 mice by using a combination of metabonomics and 16S rRNA gene sequencing technology. Nuclear magnetic resonance (NMR)-based metabonomics showed significant hepatic and urinary metabolic phenotype changes between MCD-diet fed mice and the healthy controls. A total of eight and thirteen metabolites were identified as differential metabolites associated with NASH in liver tissue and urine of mice, respectively. The proposed pathways mainly included pyrimidine metabolism, one-carbon metabolism, amino acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle and synthesis and degradation of ketone bodies. Furthermore, 16S rRNA gene sequencing analysis delineated remarkable variations in gut microbiota profiles in response to MCD diet in mice and forty differential bacterial taxa related to NASH were found between the control and model group. Puerarin could improve hepatic steatosis and inflammation in NASH mice via partially ameliorating metabolic disorders and rebalancing the gut flora. Specifically, puerarin could inhibit lipopolysaccharide (LPS)-producing genus Helicobacter, and promote butyrate-producing genus Roseburia. These findings offered novel insights into the in-depth understanding of the pathogenesis of NASH and provided further evidence for the potential use of puerarin as an anti-NASH agent.
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Affiliation(s)
- Meng-Juan Gong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Cai-Yan Zhu
- The Sixth Affilicated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Zhong-Jie Zou
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Bin Han
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ping Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
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25
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Tang J, Xiong K, Zhang T, Han Han. Application of Metabolomics in Diagnosis and Treatment of Chronic Liver Diseases. Crit Rev Anal Chem 2020; 52:906-916. [PMID: 33146026 DOI: 10.1080/10408347.2020.1842172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic liver disease represents stepwise destruction of the liver parenchyma after chronic liver injury, which is often difficult to be diagnosed accurately. Thus, the development of specific biomarkers of chronic liver disease is important. Metabolomics is a powerful tool for biomarker exploration, which enables the exploration of disease pathogenesis or drug action mechanisms at the global metabolic level. The metabolomics workflow generally includes collection, preparation, and analysis of samples, and data processing and bioinformatics. A metabolomics study can simultaneously detect the dysfunctions in the glucose, lipid, amino-acid, and nucleotide metabolisms. Hence, it facilitates the obtaining of a better understanding of the pathogenesis of chronic liver disease and its diagnosis. Many effective drugs could reverse the change of comprehensive biochemical phenotypes induced by chronic liver disease. They can even potentially restore the normal metabolic signatures of patients. Increasingly more researchers have begun to apply metabolomics technologies to diagnose chronic liver disease and investigate the mechanism of action of effective drugs or the variations in drug responses. We are convinced that deepening the understanding of the metabolic alterations could extend their use as powerful biomarkers, promoting the more effective clinical diagnosis and treatment of chronic liver disease in the future.
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Affiliation(s)
- Jie Tang
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Xiong
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Zhang
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Han Han
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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26
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Mukherjee S. Role of betaine in liver disease-worth revisiting or has the die been cast? World J Gastroenterol 2020; 26:5745-5748. [PMID: 33132631 PMCID: PMC7579752 DOI: 10.3748/wjg.v26.i38.5745] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/25/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries due to the epidemic of obesity and insulin resistance. Unfortunately, no medication is approved for NASH and risk factor modification is often advised. Over the last decade, several clinical trials on NASH have been conducted with several ongoing and the future looks promising. Although betaine (trimethyl glycine) was evaluated for NASH, results were mixed in the clinical trials in large part due to the quality of the studies. It seems reasonable to re-evaluate betaine in clinical trials for NASH and alcoholic liver disease due to its low cost, tolerability and mechanism of action.
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Affiliation(s)
- Sandeep Mukherjee
- Department of Medicine, Creighton University Medical Center, Division of Gastroenterology, Omaha, NE 68124, United States
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27
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León-Mimila P, Villamil-Ramírez H, Li XS, Shih DM, Hui ST, Ocampo-Medina E, López-Contreras B, Morán-Ramos S, Olivares-Arevalo M, Grandini-Rosales P, Macías-Kauffer L, González-González I, Hernández-Pando R, Gómez-Pérez F, Campos-Pérez F, Aguilar-Salinas C, Larrieta-Carrasco E, Villarreal-Molina T, Wang Z, Lusis AJ, Hazen SL, Huertas-Vazquez A, Canizales-Quinteros S. Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes. DIABETES & METABOLISM 2020; 47:101183. [PMID: 32791310 DOI: 10.1016/j.diabet.2020.07.010] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 07/08/2020] [Accepted: 07/28/2020] [Indexed: 12/23/2022]
Abstract
AIMS Trimethylamine N-oxide (TMAO), choline and betaine serum levels have been associated with metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). These associations could be mediated by insulin resistance. However, the relationships among these metabolites, insulin resistance and NAFLD have not been thoroughly investigated. Moreover, it has recently been suggested that TMAO could play a role in NAFLD by altering bile acid metabolism. We examined the association between circulating TMAO, choline and betaine levels and NAFLD in obese subjects. METHODS Serum TMAO, choline, betaine and bile acid levels were measured in 357 Mexican obese patients with different grades of NAFLD as determined by liver histology. Associations of NAFLD with TMAO, choline and betaine levels were tested. Moreover, association of TMAO levels with non-alcoholic steatohepatitis (NASH) was tested separately in patients with and without T2D. RESULTS TMAO and choline levels were significantly associated with NAFLD histologic features and NASH risk. While increased serum TMAO levels were significantly associated with NASH in patients with T2D, in non-T2D subjects this association lost significance after adjusting for sex, BMI and HOMA2-IR. Moreover, circulating secondary bile acids were associated both with increased TMAO levels and NASH. CONCLUSIONS In obese patients, circulating TMAO levels were associated with NASH mainly in the presence of T2D. Functional studies are required to evaluate the role of insulin resistance and T2D in this association, both highly prevalent in NASH patients.
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Affiliation(s)
- P León-Mimila
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - H Villamil-Ramírez
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - X S Li
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - D M Shih
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - S T Hui
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - E Ocampo-Medina
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - B López-Contreras
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - S Morán-Ramos
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico; Cátedras, CONACyT, Mexico City, Mexico
| | - M Olivares-Arevalo
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - P Grandini-Rosales
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - L Macías-Kauffer
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico
| | - I González-González
- Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Dr. Rubén Lénero, Mexico City, Mexico
| | - R Hernández-Pando
- Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico
| | - F Gómez-Pérez
- Departamento de Endocrinología, INCMNSZ, Mexico City, Mexico
| | - F Campos-Pérez
- Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Dr. Rubén Lénero, Mexico City, Mexico
| | - C Aguilar-Salinas
- Departamento de Endocrinología, INCMNSZ, Mexico City, Mexico; Unidad de Investigación en Enfermedades Metabólicas, INCMNSZ, Mexico City, Mexico; Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Nuevo Leon 64710, Mexico
| | | | - T Villarreal-Molina
- Laboratorio de Genómica de Enfermedades Cardiovasculares, INMEGEN, Mexico City, Mexico
| | - Z Wang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - A J Lusis
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - S L Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA
| | - A Huertas-Vazquez
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA.
| | - S Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, Mexico.
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28
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Caussy C, Chuang JC, Billin A, Hu T, Wang Y, Subramanian GM, Djedjos CS, Myers RP, Dennis EA, Loomba R. Plasma eicosanoids as noninvasive biomarkers of liver fibrosis in patients with nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2020; 13:1756284820923904. [PMID: 32523627 PMCID: PMC7257854 DOI: 10.1177/1756284820923904] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 03/23/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Eicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis. METHODS Our analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial. RESULTS At baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77). CONCLUSION This study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH.
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Affiliation(s)
- Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA
Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France,Hospices Civils de Lyon, Département
Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Pierre-Bénite,
France
| | | | | | - Tao Hu
- Gilead Sciences, Inc., Foster City, CA,
USA
| | - Ya Wang
- Gilead Sciences, Inc., Foster City, CA,
USA
| | | | | | | | - Edward A. Dennis
- Department of Pharmacology and Department of
Chemistry and Biochemistry, University of California San Diego, 9500 Gilman
Drive, MC 0601, La Jolla, CA 92093-0601, USA
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29
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Porter Starr KN, Connelly MA, Orenduff MC, McDonald SR, Sloane R, Huffman KM, Kraus WE, Bales CW. Impact on cardiometabolic risk of a weight loss intervention with higher protein from lean red meat: Combined results of 2 randomized controlled trials in obese middle-aged and older adults. J Clin Lipidol 2019; 13:920-931. [PMID: 31771921 DOI: 10.1016/j.jacl.2019.09.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 09/09/2019] [Accepted: 09/26/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND The recognized benefits of a higher protein diet on muscle mass and strength in older adults are tempered by concerns of the potentially negative cardiometabolic impact of dietary sources of animal protein. OBJECTIVE The aim of this study was to explore the cardiometabolic impact of 2 weight reduction diets: a higher protein diet, providing balanced portions of lean beef and pork throughout the day, vs. a diet following the Recommended Daily Allowance level of protein in obese middle-aged and older adults. METHODS Data from Measuring Eating, Activity and Strength: Understanding the Response-Using Protein and Protein Optimization in Women Enables Results-Using Protein were combined for the present analysis. Subjects were randomly assigned to a 6-month weight loss diet (500 kcal deficit) and prescribed a Recommended Daily Allowance level of protein (0.8 g protein/kg BW), control group, or a higher level of protein (1.2 g protein/kg BW), protein group. For the protein group, lean, high-quality protein was evenly distributed between meals or balanced throughout the day (30 g protein/meal). The following cardiometabolic markers were quantified by nuclear magnetic resonance spectroscopy: lipids, lipoproteins, GlycA, trimethylamine-N-oxide, betaine, branched-chain amino acids, and lipoprotein insulin resistance index scores. RESULTS In both groups (control [n = 27] and protein [n = 53]), there were significant (P ≤ .05) changes from baseline in weight loss (-6.2% and -7.2%), distance walked (+53.1 and +75.0 meters), and fasting plasma glucose (-7.5 and -6.2 mg/dL), respectively. At endpoint, protein group had significantly (P ≤ .05) lower triglycerides (-17.3 mg/dL), large very-low-density lipoprotein particle concentration (VLDL-P; -1.2 nmol/L), total low-density lipoprotein particle concentration (LDL-P; -67.8 nmol/L), small LDL-P (-59.4 nmol/L) and lipoprotein insulin resistance index (-5.9), whereas control group had significantly (P ≤ .05) lower GlycA (-13.1 μmol/L), total VLDL-P (-7.9 nmol/L), and small VLDL-P (-7.0 nmol/L). Differences between groups were observed for small VLDL-P (P = .02) and protein intake (P < .0001). CONCLUSIONS These findings suggest that a hypocaloric diet with either traditional (0.8 g/kg BW/d) or higher protein (1.2 g/kg BW/d; predominantly from lean red meat) content improves risk markers of cardiovascular disease and type II diabetes in obese middle-aged and older adults. Both diets were also associated with improved physical function, and neither had an adverse impact on cardiometabolic outcomes.
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Affiliation(s)
- Kathryn N Porter Starr
- Center for the Study of Aging, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA.
| | - Margery A Connelly
- Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC, USA
| | - Melissa C Orenduff
- Center for the Study of Aging, Duke University School of Medicine, Durham, NC, USA
| | - Shelley R McDonald
- Center for the Study of Aging, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA
| | - Richard Sloane
- Center for the Study of Aging, Duke University School of Medicine, Durham, NC, USA; Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA
| | - Kim M Huffman
- Department of Medicine and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
| | - William E Kraus
- Department of Medicine and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
| | - Connie W Bales
- Center for the Study of Aging, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA
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High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study. J Clin Med 2019; 8:jcm8111813. [PMID: 31683780 PMCID: PMC6912391 DOI: 10.3390/jcm8111813] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/25/2019] [Accepted: 10/29/2019] [Indexed: 12/17/2022] Open
Abstract
Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0–1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5–4.3% and 2.5–5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x – 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9–7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44–0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32–0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM.
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Molina-Molina E, Krawczyk M, Stachowska E, Lammert F, Portincasa P. Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment. Clin Res Hepatol Gastroenterol 2019; 43:638-645. [PMID: 31196707 DOI: 10.1016/j.clinre.2019.04.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/28/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) parallels comorbidities such as metabolic syndrome, dyslipidaemia or diabetes. Although NAFLD is very prevalent in overweight-obese individuals (i.e. body mass index ≥25 kg/m2), recent studies point to the presence of NAFLD in non-obese individuals, for both the Asian (<25 kg/m2) and Caucasian (<30 kg/m2) populations. This paper discusses the pathogenic pathways and current treatment options of NAFLD in non-obese populations. In this respect, non-obese subjects also need to undergo the medical screening for NAFLD. Across the scientific community, we aim to promote the advancement of knowledge in this emerging field.
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Affiliation(s)
- Emilio Molina-Molina
- Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Stachowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-210 Szczecin, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy.
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Caussy C, Ajmera VH, Puri P, Li-Shin Hsu C, Bassirian S, Mgdsyan M, Singh S, Faulkner C, Valasek MA, Rizo E, Richards L, Brenner DA, Sirlin CB, Sanyal AJ, Loomba R. Serum metabolites detect the presence of advanced fibrosis in derivation and validation cohorts of patients with non-alcoholic fatty liver disease. Gut 2019; 68:1884-1892. [PMID: 30567742 PMCID: PMC8328048 DOI: 10.1136/gutjnl-2018-317584] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/22/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Non-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis. DESIGN This is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling. RESULTS In the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively. CONCLUSION A combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Université Lyon 1, Hospices Civils de Lyon, Lyon, California, France
| | - Veeral H Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Puneet Puri
- Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mania Mgdsyan
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Seema Singh
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Claire Faulkner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mark A Valasek
- Department of Pathology, University of California at San Diego, La Jolla, California, USA
| | - Emily Rizo
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - David A Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, California, USA
| | - Arun J Sanyal
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
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Reddam A, Mitchell CA, Dasgupta S, Kirkwood JS, Vollaro A, Hur M, Volz DC. mRNA-Sequencing Identifies Liver as a Potential Target Organ for Triphenyl Phosphate in Embryonic Zebrafish. Toxicol Sci 2019; 172:51-62. [PMID: 31368501 PMCID: PMC6813745 DOI: 10.1093/toxsci/kfz169] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 01/01/2023] Open
Abstract
Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer in the United States. Using zebrafish as a model, the overall objective of this study was to identify potential organs that might be targeted by TPHP during embryonic development. Based on mRNA-sequencing, TPHP exposure from 24 to 30 h post fertilization (hpf) and 24 to 48 hpf significantly affected the abundance of 305 and 274 transcripts, respectively, relative to vehicle (0.1% DMSO) controls. In addition to minor effects on cardiotoxicity- and nephrotoxicity-related pathways, Ingenuity Pathway Analysis (IPA) of significantly affected transcripts within 30- and 48-hpf embryos revealed that hepatotoxicity-related pathways were strongly affected following exposure to TPHP alone. Moreover, while pre-treatment with fenretinide (a retinoic acid receptor agonist) mitigated TPHP-induced pericardial edema and liver enlargement at 72 hpf and 128 hpf, respectively, IPA revealed that fenretinide was unable to block TPHP-induced effects on cardiotoxicity-, nephrotoxicity-, and hepatotoxicity-related pathways at 48 hpf, suggesting that TPHP-induced effects on the transcriptome were not associated with toxicity later in development. In addition, based on Oil Red O staining, we found that exposure to TPHP nearly abolished neutral lipids from the embryonic head and trunk and, based on metabolomics, significantly decreased the total abundance of metabolites - including betaine, a known osmoprotectant - at 48 and 72 hpf. Overall, our data suggest that, in addition to the heart, TPHP exposure during early development results in adverse effects on the liver, lipid utilization, and osmoregulation within embryonic zebrafish.
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Affiliation(s)
- Aalekhya Reddam
- Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA.,Department of Environmental Sciences, University of California, Riverside, CA, USA
| | - Constance A Mitchell
- Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA.,Department of Environmental Sciences, University of California, Riverside, CA, USA
| | - Subham Dasgupta
- Department of Environmental Sciences, University of California, Riverside, CA, USA
| | - Jay S Kirkwood
- Metabolomics Core Facility, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA
| | - Alyssa Vollaro
- Metabolomics Core Facility, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA
| | - Manhoi Hur
- Metabolomics Core Facility, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA
| | - David C Volz
- Department of Environmental Sciences, University of California, Riverside, CA, USA
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Liu Y, Li Q, Wang H, Zhao X, Li N, Zhang H, Chen G, Liu Z. Fish oil alleviates circadian bile composition dysregulation in male mice with NAFLD. J Nutr Biochem 2019; 69:53-62. [PMID: 31055233 DOI: 10.1016/j.jnutbio.2019.03.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/22/2019] [Accepted: 03/12/2019] [Indexed: 02/07/2023]
Abstract
Our previous studies have found that fish oil rich in ω-3 polyunsaturated fatty acids (ω-3 PUFA) protects against non-alcoholic fatty liver disease (NAFLD) in mice. This study was aimed to explore the effects of fish oil on high fat diet (HFD)-induced circadian bile composition chaos. Male C57BL/6 mice were randomly divided into three groups, a control group (CON), a HFD group and a fish oil (FO) group, which were fed a normal chow diet, a HFD, and a HFD supplemented with FO, respectively for 12 weeks. At the end of the experiment, liver tissue, blood and bile samples were processed at 12-h intervals with the first one at zeitgeber time 0 (ZT0) and the second at zeitgeber time 12 (ZT12). Metabolites in bile were determined using UPLC-QTOF-MS, screened using multivariate statistical analysis, and analyzed using KEGG database and Metaboanalyst. The expression levels of key proteins in bile acid metabolism were examined using western blot. Results of biochemical analysis and H&E staining illustrated that feeding of HFD induced NAFLD, which was ameliorated in FO group. The bile content of each group at ZT0 (CON, HFD, or FO group) was respectively higher than that at ZT12 (P<.05). The metabolic pathway analysis of differential metabolites showed that these differences were correlated with amino acid metabolism, fatty acid biosynthesis and primary bile acid synthesis at ZT0. FO supplement could modify bile composition, which was related to the influence of its ω-3 PUFA on liver metabolism. ω-3 PUFA may also regulate the circadian rhythm of bile metabolism.
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Affiliation(s)
- Yang Liu
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China
| | - Qi Li
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China
| | - Hualin Wang
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Xiuju Zhao
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China
| | - Na Li
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China
| | - Hongyu Zhang
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China
| | - Guoxun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN, United States
| | - Zhiguo Liu
- Hubei Province Engineering Research Center of Healthy Food, School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China.
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Maternal betaine protects rat offspring from glucocorticoid-induced activation of lipolytic genes in adipose tissue through modification of DNA methylation. Eur J Nutr 2019; 59:1707-1716. [DOI: 10.1007/s00394-019-02025-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 06/08/2019] [Indexed: 12/19/2022]
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Carulli L, Zanca G, Schepis F, Villa E. The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD). Metabolites 2019; 9:25. [PMID: 30717274 PMCID: PMC6409793 DOI: 10.3390/metabo9020025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/26/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
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Affiliation(s)
- Lucia Carulli
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Giulia Zanca
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Filippo Schepis
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Erica Villa
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
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Zhang L, Qi Y, ALuo Z, Liu S, Zhang Z, Zhou L. Betaine increases mitochondrial content and improves hepatic lipid metabolism. Food Funct 2019; 10:216-223. [PMID: 30534761 DOI: 10.1039/c8fo02004c] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The liver plays a critical role in lipid metabolism. Hepatic dysfunction is not only the direct cause of fatty liver disease, but the main risk factor for obesity, diabetes, and other metabolic diseases. So far, therapeutic strategies against fatty liver disease are very limited. Betaine is a methyl donor. Current studies reported that the intake of betaine decreases body fat and is beneficial for treatment of fatty liver disease and metabolic syndrome. However, the underlying mechanisms remain largely unknown. In this study, to investigate the role of betaine on hepatic lipid metabolism and explore the underlying mechanism, HepG2 cells were cultured with fatty acids and betaine. The data indicated that betaine inhibited hepatic fat accumulation and promoted mitochondrial content and activity, suggesting that betaine is involved in the regulation of lipid and energy metabolism. Gene expression analysis implied that betaine inhibits fatty acid synthesis, but stimulates fatty acid oxidation and lipid secretion. Further, to study the mechanism of betaine, FTO (RNA demethylase) and its mutant (loss of demethylase activity) were used. The results showed that FTO blocked the ability of betaine to regulate lipid metabolism and mitochondrial content, but the FTO mutant had no effect, suggesting that betaine influences RNA methylation. This work links betaine administration with mitochondrial activity and RNA methylation, and provides a potential target for the development of new therapeutic strategies for the treatment of fatty liver disease.
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Affiliation(s)
- Lifang Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, P.R. China.
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Liver DNA methylation of FADS2 associates with FADS2 genotype. Clin Epigenetics 2019; 11:10. [PMID: 30654845 PMCID: PMC6337806 DOI: 10.1186/s13148-019-0609-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 01/04/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. METHODS DNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m2) using the Infinium HumanMethylation450 BeadChip (Illumina). Associations between DNA methylation levels and estimated delta-6 and delta-5 desaturase enzyme activities, liver histology, hepatic mRNA expression, FADS1/2 genotypes, and erythrocyte folate levels were analyzed. RESULTS We found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616. CONCLUSIONS Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation.
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 400] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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Pietzner M, Budde K, Homuth G, Kastenmüller G, Henning AK, Artati A, Krumsiek J, Völzke H, Adamski J, Lerch MM, Kühn JP, Nauck M, Friedrich N. Hepatic Steatosis Is Associated With Adverse Molecular Signatures in Subjects Without Diabetes. J Clin Endocrinol Metab 2018; 103:3856-3868. [PMID: 30060179 DOI: 10.1210/jc.2018-00999] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/24/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS Exaggerated hepatic triglyceride accumulation (i.e., hepatic steatosis) represents a strong risk factor for type 2 diabetes mellitus and cardiovascular disease. Despite the clear association of hepatic steatosis with impaired insulin signaling, the precise molecular mechanisms involved are still under debate. We combined data from several metabolomics techniques to gain a comprehensive picture of molecular alterations related to the presence of hepatic steatosis in a diabetes-free sample (N = 769) of the population-based Study of Health in Pomerania. METHODS Liver fat content (LFC) was assessed using MRI. Metabolome measurements of plasma and urine samples were done by mass spectrometry and nuclear magnetic resonance spectroscopy. Linear regression analyses were used to detect significant associations with either LFC or markers of hepatic damage. Possible mediations through insulin resistance, hypertriglyceridemia, and inflammation were tested. A predictive molecular signature of hepatic steatosis was established using regularized logistic regression. RESULTS The LFC-associated atherogenic lipid profile, tightly connected to shifts in the phospholipid content, and a prediabetic amino acid cluster were mediated by insulin resistance. Molecular surrogates of oxidative stress and multiple associations with urine metabolites (e.g., indicating altered cortisol metabolism or phase II detoxification products) were unaffected in mediation analyses. Incorporation of urine metabolites slightly improved classification of hepatic steatosis. CONCLUSIONS Comprehensive metabolic profiling allowed us to reveal molecular patterns accompanying hepatic steatosis independent of the known hallmarks. Novel biomarkers from urine (e.g., cortisol glucuronide) are worthwhile for follow-up in patients suffering from more severe liver impairment compared with our merely healthy population-based sample.
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Affiliation(s)
- Maik Pietzner
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Kathrin Budde
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine and University Greifswald, Greifswald, Germany
| | - Gabi Kastenmüller
- Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Ann-Kristin Henning
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Anna Artati
- Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany
| | - Jan Krumsiek
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Henry Völzke
- German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Diabetes Research (DZD), Site Greifswald, Greifswald, Germany
| | - Jerzy Adamski
- Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Site Greifswald, Greifswald, Germany
- Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Jens P Kühn
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
- Institute of Diagnostic Radiology, University Medicine, Carl Gustav Carus University, Dresden, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Nele Friedrich
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
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Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, Bassirian S, Hooker J, Sy E, Richards L, Schork N, Schnabl B, Brenner DA, Sirlin CB, Chen CH, Loomba R. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 2018; 68:918-932. [PMID: 29572891 PMCID: PMC6151296 DOI: 10.1002/hep.29892] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/21/2018] [Accepted: 03/20/2018] [Indexed: 12/21/2022]
Abstract
Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG :0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG :0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Université Lyon 1, Hospices Civils de Lyon, Lyon, France
| | - Cynthia Hsu
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Min-Tzu Lo
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Amy Liu
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | | | - Veeral H. Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Ethan Sy
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Nicholas Schork
- Human Biology, J. Craig Venter Institute, La Jolla, California
| | - Bernd Schnabl
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - David A. Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Chi-Hua Chen
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California
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Ashraf NU, Altaf M. Epigenetics: An emerging field in the pathogenesis of nonalcoholic fatty liver disease. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 778:1-12. [PMID: 30454678 DOI: 10.1016/j.mrrev.2018.07.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 07/17/2018] [Accepted: 07/25/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health concern associated with increased mortality due to cardiovascular disease, type II diabetes, insulin resistance, liver disease, and malignancy. The molecular mechanism underlying these processes is not fully understood but involves hepatic fat accumulation and alteration of energy metabolism and inflammatory signals derived from various cell types including immune cells. During the last two decades, epigenetic mechanisms have emerged as important regulators of chromatin alteration and the reprogramming of gene expression. Recently, epigenetic mechanisms have been implicated in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) genesis. Epigenetic mechanisms could be used as potential therapeutic targets and as noninvasive diagnostic biomarkers for NAFLD. These mechanisms can determine disease progression and prognosis in NAFLD. In this review, we discuss the role of epigenetic mechanisms in the progression of NAFLD and potential therapeutic targets for the treatment of NAFLD.
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Affiliation(s)
- Nissar U Ashraf
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
| | - Mohammad Altaf
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India.
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43
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Zhao G, He F, Wu C, Li P, Li N, Deng J, Zhu G, Ren W, Peng Y. Betaine in Inflammation: Mechanistic Aspects and Applications. Front Immunol 2018; 9:1070. [PMID: 29881379 PMCID: PMC5976740 DOI: 10.3389/fimmu.2018.01070] [Citation(s) in RCA: 274] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 04/30/2018] [Indexed: 12/12/2022] Open
Abstract
Betaine is known as trimethylglycine and is widely distributed in animals, plants, and microorganisms. Betaine is known to function physiologically as an important osmoprotectant and methyl group donor. Accumulating evidence has shown that betaine has anti-inflammatory functions in numerous diseases. Mechanistically, betaine ameliorates sulfur amino acid metabolism against oxidative stress, inhibits nuclear factor-κB activity and NLRP3 inflammasome activation, regulates energy metabolism, and mitigates endoplasmic reticulum stress and apoptosis. Consequently, betaine has beneficial actions in several human diseases, such as obesity, diabetes, cancer, and Alzheimer's disease.
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Affiliation(s)
- Guangfu Zhao
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Fang He
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Chenlu Wu
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Pan Li
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Nengzhang Li
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Jinping Deng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, Subtropical Institute of Animal Nutrition and Feed, South China Agricultural University, Guangzhou, Guangdong, China
| | - Guoqiang Zhu
- Jiangsu Co-Innovation Center for Important Animal Infectious Diseases and Zoonoses, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Wenkai Ren
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, Subtropical Institute of Animal Nutrition and Feed, South China Agricultural University, Guangzhou, Guangdong, China
- Jiangsu Co-Innovation Center for Important Animal Infectious Diseases and Zoonoses, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Yuanyi Peng
- College of Animal Science and Technology, Southwest University, Chongqing, China
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Pirola CJ, Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity. World J Gastroenterol 2018; 24:1601-1615. [PMID: 29686467 PMCID: PMC5910543 DOI: 10.3748/wjg.v24.i15.1601] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/13/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
This review intends to uncover how information from large-scale genetic profiling (whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease (NAFLD), as well as information from circulating transcriptomics (cell-free miRNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.
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Affiliation(s)
- Carlos J Pirola
- Department of Genetics and Molecular Biology of Complex Diseases. University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
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45
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Gitto S, Schepis F, Andreone P, Villa E. Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives. Metabolites 2018; 8:17. [PMID: 29495258 PMCID: PMC5876006 DOI: 10.3390/metabo8010017] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 02/19/2018] [Accepted: 02/22/2018] [Indexed: 12/14/2022] Open
Abstract
In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.
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Affiliation(s)
- Stefano Gitto
- Department of Medical and Surgical Sciences, University of Bologna and Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, 40138 Bologna, Italy.
- Research Centre for the Study of Hepatitis, University of Bologna, 40138 Bologna, Italy.
| | - Filippo Schepis
- Department of Gastroenterology, Azienda Ospedaliero-Universitaria and University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, University of Bologna and Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, 40138 Bologna, Italy.
- Research Centre for the Study of Hepatitis, University of Bologna, 40138 Bologna, Italy.
| | - Erica Villa
- Department of Gastroenterology, Azienda Ospedaliero-Universitaria and University of Modena and Reggio Emilia, 41124 Modena, Italy.
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Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol 2018; 68:268-279. [PMID: 29122391 DOI: 10.1016/j.jhep.2017.09.003] [Citation(s) in RCA: 638] [Impact Index Per Article: 91.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/01/2017] [Accepted: 09/04/2017] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
| | - Luca Valenti
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Sweden.
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Zhao F. Dysregulated Epigenetic Modifications in the Pathogenesis of NAFLD-HCC. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1061:79-93. [DOI: 10.1007/978-981-10-8684-7_7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Metwally M, Eslam M, George J. Genetic and Epigenetic Associations of NAFLD: Focus on Clinical Decision Making. CURRENT HEPATOLOGY REPORTS 2017; 16:335-345. [DOI: 10.1007/s11901-017-0372-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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49
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Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol 2017; 23:1-12. [PMID: 28268262 PMCID: PMC5381829 DOI: 10.3350/cmh.2016.0109] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 11/04/2016] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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50
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Hu Y, Sun Q, Liu J, Jia Y, Cai D, Idriss AA, Omer NA, Zhao R. In ovo injection of betaine alleviates corticosterone-induced fatty liver in chickens through epigenetic modifications. Sci Rep 2017; 7:40251. [PMID: 28059170 PMCID: PMC5216338 DOI: 10.1038/srep40251] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/05/2016] [Indexed: 12/29/2022] Open
Abstract
Betaine alleviates high-fat diet-induced fatty liver and prenatal betaine programs offspring hepatic lipid metabolism. Excessive corticosterone (CORT) exposure causes fatty liver in chickens, yet it remains unknown whether and how prenatal betaine modulates the susceptibility of CORT-induced fatty liver later in life. In this study, fertilized eggs were injected with saline or betaine before incubation, and the hatchlings were raised at 8 weeks of age followed by 7 days of subcutaneous CORT injection. CORT-induced fatty liver was less severe in betaine-treated chickens, with significantly reduced oil-red staining and hepatic triglyceride content (P < 0.05). The protective effect of prenatal betaine was associated with significantly up-regulated expression of PPARα and CPT1α, as well as mitochondrial DNA (mtDNA)-encoded genes (P < 0.05). Moreover, betaine rescued CORT-induced alterations in methionine cycle genes, which coincided with modifications of CpG methylation on CPT1α gene promoter and mtDNA D-loop regions. Furthermore, the elevation of hepatic GR protein content after CORT treatment was significantly reduced (P < 0.05), while the reduction of GR binding to the control region of affected genes was significantly increased (P < 0.05), in betaine-treated chickens. These results indicate that in ovo betaine injection protects the juvenile chickens from CORT-induced fatty liver.
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Affiliation(s)
- Yun Hu
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Qinwei Sun
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Jie Liu
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Yimin Jia
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Demin Cai
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Abdulrahman A Idriss
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Nagmeldin A Omer
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Ruqian Zhao
- Key Laboratory of Animal Physiology &Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China.,Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, Nanjing 210095, P. R. China
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