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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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Lucitti JL, Laudermilk LT, Amato GS, Maitra R. The Monoacylglycerol Lipase Inhibitor ABX-1431 Does Not Improve Alcoholic Liver Disease. Cannabis Cannabinoid Res 2024; 9:e1179-e1183. [PMID: 37253145 DOI: 10.1089/can.2023.0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023] Open
Abstract
Introduction: Excessive alcohol consumption can result in alcoholic liver disease (ALD). There is no FDA-approved drug to specifically treat ALD and current management approaches have limited efficacy. Past studies indicate that monoacylglycerol lipase (MAGL) inhibition can have a positive impact on nonalcoholic fatty liver disease. However, the effect of MAGL inhibition in ALD has not been reported. Materials and Methods: We tested the highly selective and clinically evaluated MAGL inhibitor ABX-1431 in the Lieber-DeCarli liquid alcohol diet-induced model of ALD in C57BL/6 mice. Results: ABX-1431 failed to reduce ALD-associated steatosis and elevated levels of liver enzymes associated with hepatic injury. Furthermore, survival rate declined with increasing doses of ABX-1431 when compared with mice administered vehicle only. Conclusion: These data suggest that MAGL inhibition does not improve ALD and is unlikely to be a good strategy for this condition.
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Affiliation(s)
- Jennifer L Lucitti
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Lucas T Laudermilk
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - George S Amato
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Rangan Maitra
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
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Zhuge H, Pan Y, Lai S, Chang K, Ding Q, Cao W, Song Q, Li S, Dou X, Ding B. Penthorum chinense Pursh extract ameliorates alcohol-related fatty liver disease in mice via the SIRT1/AMPK signaling axis. Heliyon 2024; 10:e31195. [PMID: 38832279 PMCID: PMC11145240 DOI: 10.1016/j.heliyon.2024.e31195] [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: 12/08/2023] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 06/05/2024] Open
Abstract
Penthorum chinense Pursh (P. chinense), a functional food, has been applied to protect the liver against alcohol-related fatty liver disease (ALD) for a long history in China. This study was designed to evaluate the ameliorative activity of the polyphenolic fraction in P. chinense (PGF) depending on the relief of ALD. The ALD mouse model was established by exposing the mice to a Lieber-DeCarli alcohol liquid diet. We found that PGF administration significantly ameliorated alcohol-induced liver injury, steatosis, oxidative stress, and inflammation in mice. Furthermore, alcohol-increased levels of the critical hepatic lipid synthesis proteins sterol regulatory element binding transcription factor (SREBP-1) and diacylglycerol o-acyltransferase 2 (DGAT2) were attenuated by PGF. Similarly, PGF inhibited the expression of the lipid transport protein very low-density lipoprotein receptor (VLDLR). Interestingly, PGF restored alcohol-inhibited expression of carnitine palmitoyltransferase 1 (CPT1) and peroxisome proliferator-activated receptor alpha (PPARα), essential fatty acid β-oxidation proteins. Mechanistic studies revealed that PGF protects against alcohol-induced hepatocyte injury and lipid deposition via the SIRT1/AMPK signaling pathway. In sum, this research clearly demonstrated the protective effects of PGF against ALD, which was mediated by activating SIRT1/AMPK pathways in hepatocytes. We provide a new theoretical basis for using P. chinense as a functional food in ALD.
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Affiliation(s)
- Hui Zhuge
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yan Pan
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Shanglei Lai
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Kaixin Chang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qinchao Ding
- College of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- College of Animal Science, Zhejiang University, Hangzhou, 310058, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wenjing Cao
- College of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qing Song
- College of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Songtao Li
- College of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaobing Dou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Bin Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
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4
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Mahalingam S, Bellamkonda R, Kharbanda KK, Arumugam MK, Kumar V, Casey CA, Leggio L, Rasineni K. Role of ghrelin hormone in the development of alcohol-associated liver disease. Biomed Pharmacother 2024; 174:116595. [PMID: 38640709 PMCID: PMC11161137 DOI: 10.1016/j.biopha.2024.116595] [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: 01/25/2024] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024] Open
Abstract
Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.
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Affiliation(s)
- Sundararajan Mahalingam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ramesh Bellamkonda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vikas Kumar
- Mass Spectrometry and Proteomic Core Facility, University of Nebraska Medical Center, Omaha, NE, USA; Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Carol A Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Bethesda, Baltimore, MD, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
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5
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Zhang H, Yan X, Lin A, Xia P, Su Y. Inhibition of ghrelin activity by the receptor antagonist [D-Lys3]-GHRP-6 enhances hepatic fatty acid oxidation and gluconeogenesis in a growing pig model. Peptides 2023; 166:171041. [PMID: 37301480 DOI: 10.1016/j.peptides.2023.171041] [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: 03/28/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023]
Abstract
Despite its central role in regulating energy intake and metabolism, ghrelin is little understood when it comes to its effects on hepatic lipid and glucose metabolism. Growing pigs were intravenously injected with ghrelin receptor antagonist [D-Lys3]-GHRP-6 (DLys; 6 mg/kg body weight) for seven days to determine whether ghrelin plays a role in glucose and lipid metabolism. DLys treatment significantly reduced body weight gain and adipose histopathology found that DLys treatment dramatically reduced adipocyte size. DLys treatment significantly increased serum NEFA and insulin levels, hepatic glucose level and HOMA-IR, and significantly decreased serum TBA level of growing pigs after fasting. Moreover, DLys treatment changed the dynamics of serum metabolic parameters, including glucose, NEFA, TBA, insulin, GH, leptin, and cortisol. Liver transcriptome showed that DLys treatment affected the metabolism-related pathways. Compared with the control group, adipose tissue lipolysis (the adipose triglyceride lipase level was significantly increased), hepatic gluconeogenesis (the G6PC protein level was significantly increased) and fatty acid oxidation (the CPT1A protein level was significantly increased) were promoted in the DLys group. DLys treatment expanded degrees of oxidative phosphorylation in the liver, coming about in a higher NAD+ /NADH proportion and enactment of the SIRT1 signaling pathway. Additionally, the liver protein levels of the DLys group were significantly higher than those of the control group for GHSR, PPAR alpha, and PGC-1. To summarize, inhibition of ghrelin activity can significantly affect metabolism and alter energy levels by enhancing fat mobilization, hepatic fatty acid oxidation and gluconeogenesis without affecting fatty acid uptake and synthesis in the liver.
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Affiliation(s)
- He Zhang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China; College of Life Sciences, Xuzhou Medical University, 221004 Xuzhou, China
| | - Xiaoxi Yan
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Ailian Lin
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Pengke Xia
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Yong Su
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China.
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6
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Singh TP, Kadyan S, Devi H, Park G, Nagpal R. Gut microbiome as a therapeutic target for liver diseases. Life Sci 2023; 322:121685. [PMID: 37044173 DOI: 10.1016/j.lfs.2023.121685] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/27/2023] [Accepted: 04/05/2023] [Indexed: 04/14/2023]
Abstract
The prominent role of gut in regulating the physiology of different organs in a human body is increasingly acknowledged, to which the bidirectional communication between gut and liver is no exception. Liver health is modulated via different key components of gut-liver axis. The gut-derived products mainly generated from dietary components, microbial metabolites, toxins, or other antigens are sensed and transported to the liver through portal vein to which liver responds by secreting bile acids and antibodies. Therefore, maintaining a healthy gut microbiome can promote homeostasis of this gut-liver axis by regulating the intestinal barrier function and reducing the antigenic molecules. Conversely, liver secretions also regulate the gut microbiome composition. Disturbed homeostasis allows luminal antigens to reach liver leading to impaired liver functioning and instigating liver disorders. The perturbations in gut microbiome, permeability, and bile acid pool have been associated with several liver disorders, although precise mechanisms remain largely unresolved. Herein, we discuss functional fingerprints of a healthy gut-liver axis while contemplating mechanistic understanding of pathophysiology of liver diseases and plausible role of gut dysbiosis in different diseased states of liver. Further, novel therapeutic approaches to prevent the severity of liver disorders are discussed in this review.
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Affiliation(s)
- Tejinder Pal Singh
- Department of Dairy Microbiology, College of Dairy Science and Technology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India
| | - Saurabh Kadyan
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA
| | - Harisha Devi
- Department of Dairy Microbiology, College of Dairy Science and Technology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India
| | - Gwoncheol Park
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA
| | - Ravinder Nagpal
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA.
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Jia L. Dietary cholesterol in alcohol-associated liver disease. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00026. [PMID: 37152117 PMCID: PMC10158609 DOI: 10.1097/in9.0000000000000026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/13/2023] [Indexed: 05/09/2023]
Abstract
There is an increasing prevalence of alcohol-associated liver disease (ALD) worldwide. In addition to excessive alcohol consumption, other nutritional factors have been shown to affect the initiation and progression of ALD. The emerging role of cholesterol in exacerbating ALD has been reported recently and the underlying mechanisms are discussed. In addition, the interplay between dietary cholesterol and alcohol on cholesterol metabolism is reviewed. Furthermore, we highlight the therapeutic potential of cholesterol-lowering drugs in managing the onset and severity of ALD. Finally, we suggest the future mechanistic investigation of the effect of cholesterol on insulin resistance and intestinal inflammation in the exacerbation of alcohol-induced cellular and systemic dysfunction.
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Affiliation(s)
- Lin Jia
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
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8
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Arumugam MK, Perumal SK, Rasineni K, Donohue TM, Osna NA, Kharbanda KK. Lipidomic Analysis of Liver Lipid Droplets after Chronic Alcohol Consumption with and without Betaine Supplementation. BIOLOGY 2023; 12:462. [PMID: 36979154 PMCID: PMC10045066 DOI: 10.3390/biology12030462] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 03/04/2023] [Accepted: 03/08/2023] [Indexed: 03/19/2023]
Abstract
The earliest manifestation of alcohol-associated liver disease is hepatic steatosis, which is characterized by fat accumulation in specialized organelles called lipid droplets (LDs). Our previous studies reported that alcohol consumption elevates the numbers and sizes of LDs in hepatocytes, which is attenuated by simultaneous treatment with the methyl group donor, betaine. Here, we examined changes in the hepatic lipidome with respect to LD size and dynamics in male Wistar rats fed for 6 weeks with control or ethanol-containing liquid diets that were supplemented with or without 10 mg betaine/mL. At the time of sacrifice, three hepatic LD fractions, LD1 (large droplets), LD2 (medium-sized droplets), and LD3 (small droplets) were isolated from each rat. Untargeted lipidomic analyses revealed that each LD fraction of ethanol-fed rats had higher phospholipids, cholesteryl esters, diacylglycerols, ceramides, and hexosylceramides compared with the corresponding fractions of pair-fed controls. Interestingly, the ratio of phosphatidylcholine to phosphatidylethanolamine (the two most abundant phospholipids on the LD surface) was lower in LD1 fraction compared with LD3 fraction, irrespective of treatment; however, this ratio was significantly lower in ethanol LD fractions compared with their respective control fractions. Betaine supplementation significantly attenuated the ethanol-induced lipidomic changes. These were mainly associated with the regulation of LD surface phospholipids, ceramides, and glycerolipid metabolism in different-sized LD fractions. In conclusion, our results show that ethanol-induced changes in the hepatic LD lipidome likely stabilizes larger-sized LDs during steatosis development. Furthermore, betaine supplementation could effectively reduce the size and dynamics of LDs to attenuate alcohol-associated hepatic steatosis.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Center for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai 600119, India
| | - Sathish Kumar Perumal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- 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
- 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
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- 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
- 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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9
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Rizzo M, Colletti A, Penson PE, Katsiki N, Mikhailidis DP, Toth PP, Gouni-Berthold I, Mancini J, Marais D, Moriarty P, Ruscica M, Sahebkar A, Vinereanu D, Cicero AFG, Banach M, Al-Khnifsawi M, Alnouri F, Amar F, Atanasov AG, Bajraktari G, Banach M, Gouni-Berthold I, Bhaskar S, Bielecka-Dąbrowa A, Bjelakovic B, Bruckert E, Bytyçi I, Cafferata A, Ceska R, Cicero AF, Chlebus K, Collet X, Daccord M, Descamps O, Djuric D, Durst R, Ezhov MV, Fras Z, Gaita D, Gouni-Berthold I, Hernandez AV, Jones SR, Jozwiak J, Kakauridze N, Kallel A, Katsiki N, Khera A, Kostner K, Kubilius R, Latkovskis G, John Mancini G, David Marais A, Martin SS, Martinez JA, Mazidi M, Mikhailidis DP, Mirrakhimov E, Miserez AR, Mitchenko O, Mitkovskaya NP, Moriarty PM, Mohammad Nabavi S, Nair D, Panagiotakos DB, Paragh G, Pella D, Penson PE, Petrulioniene Z, Pirro M, Postadzhiyan A, Puri R, Reda A, Reiner Ž, Radenkovic D, Rakowski M, Riadh J, Richter D, Rizzo M, Ruscica M, Sahebkar A, Serban MC, Shehab AM, Shek AB, Sirtori CR, Stefanutti C, Tomasik T, Toth PP, Viigimaa M, Valdivielso P, Vinereanu D, Vohnout B, von Haehling S, Vrablik M, Wong ND, Yeh HI, Zhisheng J, Zirlik A. Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP). Pharmacol Res 2023; 189:106679. [PMID: 36764041 DOI: 10.1016/j.phrs.2023.106679] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
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Affiliation(s)
- Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Via del Vespro 141, 90127 Palermo, Italy.
| | - Alessandro Colletti
- Department of Science and Drug Technology, University of Turin, Turin, Italy
| | - Peter E Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK; Liverpool Centre for Cardiovascular Science, Liverpool, UK
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, Medical School, University College London (UCL), London, UK
| | - Peter P Toth
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA; Preventive Cardiology, CGH Medical Center, Sterling, IL, USA
| | - Ioanna Gouni-Berthold
- Department of Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Germany
| | - John Mancini
- Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - David Marais
- Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa
| | - Patrick Moriarty
- Division of Clinical Pharmacology, Division of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dragos Vinereanu
- Cardiology Department, University and Emergency Hospital, Bucharest, Romania, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Arrigo Francesco Giuseppe Cicero
- Hypertension and Cardiovascular disease risk research center, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy; IRCCS Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
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Arumugam MK, Chava S, Perumal SK, Paal MC, Rasineni K, Ganesan M, Donohue TM, Osna NA, Kharbanda KK. Acute ethanol-induced liver injury is prevented by betaine administration. Front Physiol 2022; 13:940148. [PMID: 36267591 PMCID: PMC9577233 DOI: 10.3389/fphys.2022.940148] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Binge drinking is the most common form of excessive alcohol use. Repeated episodes of binge drinking cause multiple organ injuries, including liver damage. We previously demonstrated that chronic ethanol administration causes a decline in the intrahepatic ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). This decline causes impairments in essential methylation reactions that result in alcohol-induced fatty liver (steatosis) and other features of alcohol-associated liver disease (ALD). Co-treatment with betaine during chronic ethanol feeding, normalizes hepatocellular SAM:SAH ratio and alleviates many features of liver damage including steatosis. Here, we sought to examine whether betaine treatment similarly protects against liver injury in an alcohol binge-drinking model. We hypothesized that ethanol binge with prior or simultaneous betaine administration would prevent or attenuate acute alcohol-induced liver damage. Male C57Bl/6 mice were gavaged twice, 12 h apart, with either 6 g ethanol/kg BW or with an equal volume/kg BW of 0.9% NaCl. Two separate groups of mice (n = 5/group) were gavaged with 4 g betaine/kg BW, either 2 h before or simultaneously with the ethanol or saline gavages. All mice were sacrificed 8 h after the last gavage and serum and liver parameters were quantified. Ethanol binges caused a 50% decrease in hepatic SAM:SAH ratio and a >3-fold rise in liver triglycerides (p ≤ 0.05). These latter changes were accompanied by elevated serum AST and ALT activities and blood alcohol concentrations (BAC) that were ∼three-times higher than the legal limit of intoxication in humans. Mice that were treated with betaine 2 h before or simultaneously with the ethanol binges exhibited similar BAC as in mice given ethanol-alone. Both betaine treatments significantly elevated hepatic SAM levels thereby normalizing the SAM:SAH ratio and attenuating hepatic steatosis and other injury parameters, compared with mice given ethanol alone. Simultaneous betaine co-administration with ethanol was more effective in preventing or attenuating liver injury than betaine given before ethanol gavage. Our findings confirm the potential therapeutic value of betaine administration in preventing liver injury after binge drinking in an animal model.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, 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
| | - Srinivas Chava
- Research Service, 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
| | - Sathish Kumar Perumal
- Research Service, 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
| | - Matthew C. Paal
- Research Service, 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
| | - Karuna Rasineni
- Research Service, 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 and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Murali Ganesan
- Research Service, 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
| | - Terrence M. Donohue
- Research Service, 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
| | - Natalia A. Osna
- Research Service, 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
| | - Kusum K. Kharbanda
- Research Service, 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 and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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11
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Baicalin ameliorates alcohol-induced hepatic steatosis by suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL. Arch Biochem Biophys 2022; 722:109236. [DOI: 10.1016/j.abb.2022.109236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/17/2022] [Accepted: 04/11/2022] [Indexed: 11/15/2022]
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12
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Lower plasma glutathione, choline, and betaine concentrations are associated with fatty liver in postmenopausal women. Nutr Res 2022; 101:23-30. [PMID: 35364359 DOI: 10.1016/j.nutres.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 11/18/2022]
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Wang C, Ma C, Gong L, Dai S, Li Y. Preventive and therapeutic role of betaine in liver disease: A review on molecular mechanisms. Eur J Pharmacol 2021; 912:174604. [PMID: 34743980 DOI: 10.1016/j.ejphar.2021.174604] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022]
Abstract
Betaine is a kind of water-soluble quaternary amine-type alkaloid widely existing in food, such as wheat germ, beet, spinach, shrimp and wolfberry. As an important methyl donor and osmotic pressure regulator in human body, betaine plays an important role in a variety of physiological activities. In recent years, a large number of literatures have shown that betaine has good preventive and therapeutic effects on many liver diseases, including chemical or drug-induced liver injury, nonalcoholic fatty liver disease, alcoholic fatty liver disease, liver fibrosis, hepatitis B and hepatitis C. Therefore, by searching the databases of Web of Science, PubMed, SciFinder and CNKI, this paper has summarized the molecular mechanisms of betaine in improving liver diseases. The results show that the improvement of liver diseases by betaine is closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, improvement of insulin resistance, reduction of endoplasmic reticulum stress, alleviation of liver oxidative stress, increase of autophagy, remodeling of intestinal flora and regulation of epigenetic modification. More importantly, nuclear transcription factor kappa (NF-κB), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α/γ (PPAR-α/γ), liver X receptor α (LXRα), protein kinase B (Akt), toll-like receptor 4 (TLR4) and cysteinyl aspartate specific proteinase-3 (Caspase-3) signaling pathways are considered as important molecular targets for betaine to improve liver diseases. These important findings will provide a direction and basis for further exploring the pathogenesis of various liver diseases and tapping the potential of betaine in the clinical treatment.
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Affiliation(s)
- Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shu Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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14
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Rehman A, Mehta KJ. Betaine in ameliorating alcohol-induced hepatic steatosis. Eur J Nutr 2021; 61:1167-1176. [PMID: 34817678 PMCID: PMC8921017 DOI: 10.1007/s00394-021-02738-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/03/2021] [Indexed: 01/15/2023]
Abstract
Alcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and/or activities of protein phosphtase-2A, FOXO1, PPAR-α, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring β-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine’s effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine’s remedial properties to treat alcohol-induced hepatic steatosis.
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Affiliation(s)
- Aisha Rehman
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
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Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem 2021; 12:87-103. [PMID: 34630912 PMCID: PMC8473419 DOI: 10.4331/wjbc.v12.i5.87] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression are still to be fully elucidated. Oxidative stress, mitochondrial dysfunction, gut dysbiosis and altered immune system response plays an important role in disease pathogenesis, triggering the activation of inflammatory pathways and apoptosis. Despite many recent clinical studies treatment options for ALD are limited, especially at the alcoholic hepatitis stage. We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.
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Affiliation(s)
- Lucy Petagine
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Vinood B Patel
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
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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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Rasineni K, Jordan CW, Thomes PG, Kubik JL, Staab EM, Sweeney SA, Talmon GA, Donohue TM, McNiven MA, Kharbanda KK, Casey CA. Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver. Front Physiol 2021; 12:625352. [PMID: 33746771 PMCID: PMC7966527 DOI: 10.3389/fphys.2021.625352] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/02/2021] [Indexed: 01/15/2023] Open
Abstract
Background: Fatty liver, a major health problem worldwide, is the earliest pathological change in the progression of alcohol-associated (AFL) and non-alcoholic fatty liver disease (NAFL). Though the causes of AFL and NAFL differ, both share similar histological and some common pathophysiological characteristics. In this study, we sought to examine mechanisms responsible for lipid dynamics in liver and adipose tissue in the setting of AFL and NAFL in response to 48 h of fasting. Methods: Male rats were fed Lieber-DeCarli liquid control or alcohol-containing diet (AFL model), chow or high-fat pellet diet (NAFL model). After 6-8 weeks of feeding, half of the rats from each group were fasted for 48 h while the other half remained on their respective diets. Following sacrifice, blood, adipose, and the liver were collected for analysis. Results: Though rats fed AFL and NAFL diets both showed fatty liver, the physiological mechanisms involved in the development of each was different. Here, we show that increased hepatic de novo fatty acid synthesis, increased uptake of adipose-derived free fatty acids, and impaired triglyceride breakdown contribute to the development of AFL. In the case of NAFL, however, increased dietary fatty acid uptake is the major contributor to hepatic steatosis. Likewise, the response to starvation in the two fatty liver disease models also varied. While there was a decrease in hepatic steatosis after fasting in ethanol-fed rats, the control, chow and high-fat diet-fed rats showed higher levels of hepatic steatosis than pair-fed counterparts. This diverse response was a result of increased adipose lipolysis in all experimental groups except fasted ethanol-fed rats. Conclusion: Even though AFL and NAFL are nearly histologically indistinguishable, the physiological mechanisms that cause hepatic fat accumulation are different as are their responses to starvation.
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Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Clayton W. Jordan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Paul G. Thomes
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Jacy L. Kubik
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Elizabeth M. Staab
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sarah A. Sweeney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Terrence M. Donohue
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, Rochester, MN, United States
| | - Kusum K. Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A. Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Le Daré B, Ferron PJ, Gicquel T. The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease? Int J Mol Sci 2021; 22:2139. [PMID: 33670021 PMCID: PMC7926651 DOI: 10.3390/ijms22042139] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases-particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this "inflammatory shift". Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.
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Affiliation(s)
- Brendan Le Daré
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
| | - Pierre-Jean Ferron
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
| | - Thomas Gicquel
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
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Rasineni K, Lee SML, McVicker BL, Osna NA, Casey CA, Kharbanda KK. Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration. BIOLOGY 2020; 10:19. [PMID: 33396223 PMCID: PMC7823640 DOI: 10.3390/biology10010019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/27/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. METHODS Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. RESULTS LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. CONCLUSION Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.
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Affiliation(s)
- Karuna Rasineni
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Serene M. L. Lee
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Benita L. McVicker
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- 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; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Carol A. Casey
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, 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; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Kirpich IA, Warner DR, Feng W, Joshi-Barve S, McClain CJ, Seth D, Zhong W, Zhou Z, Osna NA, Kharbanda KK. Mechanisms, biomarkers and targets for therapy in alcohol-associated liver injury: From Genetics to nutrition: Summary of the ISBRA 2018 symposium. Alcohol 2020; 83:105-114. [PMID: 31129175 PMCID: PMC7043088 DOI: 10.1016/j.alcohol.2019.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023]
Abstract
The symposium "Mechanisms, Biomarkers and Targets for Therapy in Alcohol-associated Liver Injury: From Genetics to Nutrition" was held at the 19th Congress of International Society for Biomedical Research on Alcoholism on September 13th, 2018 in Kyoto, Japan. The goal of the symposium was to discuss the importance of genetics and nutrition in alcoholic liver disease (ALD) development from mechanistic and therapeutic perspectives. The following is a summary of this session addressing the gene polymorphisms in ALD, the role of zinc in gut-liver axis perturbations associated with ALD, highlighting the importance of dietary fat in ALD pathogenesis, the hepatic n6 and n3 PUFA oxylipin pattern associated with ethanol-induced liver injury, and finally deliberating on new biomarkers for alcoholic hepatitis and their implications for diagnosis and therapy. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows.
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Affiliation(s)
- Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Wenke Feng
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Swati Joshi-Barve
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, And Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia
| | - Wei Zhong
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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Abstract
The last few decades have witnessed a global rise in the number of older individuals. Despite this demographic shift, morbidity within this population group is high. Many factors influence healthspan; however, an obesity pandemic is emerging as a significant determinant of older people's health. It is well established that obesity adversely affects several metabolic systems. However, due to its close association with overall cardiometabolic health, the impact that obesity has on cholesterol metabolism needs to be recognised. The aim of the present review is to critically discuss the effects that obesity has on cholesterol metabolism and to reveal its significance for healthy ageing.
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22
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Radziejewska A, Muzsik A, Milagro FI, Martínez JA, Chmurzynska A. One-Carbon Metabolism and Nonalcoholic Fatty Liver Disease: The Crosstalk between Nutrients, Microbiota, and Genetics. Lifestyle Genom 2019; 13:53-63. [PMID: 31846961 DOI: 10.1159/000504602] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/30/2019] [Indexed: 01/02/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Its etiology includes nutritional, genetic, and lifestyle factors. Several mechanisms may link one-carbon metabolism - the associated metabolic pathways of folate, methionine, and choline - to the onset of NAFLD. In this review, we attempted to assess how choline, folate, methionine, and betaine affect NAFLD development, mainly through their role in the secretion of very low-density lipoproteins (VLDL) from the liver. We also reviewed recent articles that have described the relation between microbiota metabolism and NAFLD progression. Moreover, we describe the effect of single-nucleotide polymorphisms (SNP) in genes related to one-carbon metabolism and disease prevalence. We additionally seek SNP identified by genome-wide associations that may increase the risk of this disease. Even though the evidence available is not entirely consistent, it seems that the concentrations of choline, methionine, folate, and betaine may affect the progression of NAFLD. Since there is no effective therapy for NAFLD, further investigations into the link between nutrition, gut microbiota, genetic factors, and NAFLD are still necessary, with a particular emphasis on methyl donors.
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Affiliation(s)
- Anna Radziejewska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Muzsik
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Fermín I Milagro
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - J Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland,
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23
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Zawieja EE, Zawieja B, Chmurzynska A. Betaine Supplementation Moderately Increases Total Cholesterol Levels: A Systematic Review and Meta-Analysis. J Diet Suppl 2019; 18:105-117. [DOI: 10.1080/19390211.2019.1699223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Emilia E. Zawieja
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Bogna Zawieja
- Department of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
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24
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Hagar H, Husain S, Fadda LM, Attia NM, Attia MMA, Ali HM. Inhibition of NF-κB and the oxidative stress -dependent caspase-3 apoptotic pathway by betaine supplementation attenuates hepatic injury mediated by cisplatin in rats. Pharmacol Rep 2019; 71:1025-1033. [PMID: 31590115 DOI: 10.1016/j.pharep.2019.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/08/2019] [Accepted: 06/05/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Cisplatin is a major anti-cancer drug commonly used in the treatment of various cancers; nevertheless, the associated hepatotoxicity has limited its clinical application. The aim of this investigation is to test the impact of betaine supplementation on cisplatin-induced hepatotoxicity. METHODS Animals were allocated into four groups; normal control group (control betaine group (250 mg/kg/day, po for twenty six days), cisplatin group (single injection of 7 mg/kg, ip) and betaine + cisplatin group (received betaine for twenty one days before cisplatin injection and daily after cisplatin for five days). RESULTS Cisplatin-induced liver injury was confirmed by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Cisplatin elevated lipid peroxides, and reduced the concentrations of reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase and superoxide dismutase (SOD) in hepatic tissues. Cisplatin increased the inflammatory mediators; nitrite and tumor necrosis factor-α (TNF- α) in hepatic tissues. Increased gene expressions of the apoptotic marker, caspase-3 and nuclear factor-kappa B (NF-κB) were observed in hepatic tissues of cisplatin-treated rats. All these changes were further confirmed by histopathological findings in cisplatin group. Pre-treatment with betaine reduced serum aminotransferases (ALT and AST), and lowered hepatic concentrations of lipid peroxides, nitrite and TNF-α while increased SOD, GSH, catalase, and GSH-Px concentrations. Moreover, the histological and immunohistochemical changes were improved. CONCLUSION The suppression of NF-κβ-mediated inflammation, oxidative stress, and caspase-3 induced apoptosis are possible mechanisms to the observed hepatoprotective effect of betaine.
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Affiliation(s)
- Hanan Hagar
- Pharmacology Unit, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, Pharmacy College, Zagazig University, Egypt.
| | - Sufia Husain
- Department of Pathology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Laila Mohamed Fadda
- Department of Pharmacology, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Hanaa Mahmoud Ali
- Department of Genetic and Cytology, National Research Center, Dokki, Egypt; Common First Year Deanship, King Saud University, Riyadh, Saudi Arabia
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25
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Donohue TM, Osna NA, Kharbanda KK, Thomes PG. Lysosome and proteasome dysfunction in alcohol-induced liver injury. LIVER RESEARCH 2019; 3:191-205. [DOI: 10.1016/j.livres.2019.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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26
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Rasineni K, Kubik JL, Casey CA, Kharbanda KK. Inhibition of Ghrelin Activity by Receptor Antagonist [d-Lys-3] GHRP-6 Attenuates Alcohol-Induced Hepatic Steatosis by Regulating Hepatic Lipid Metabolism. Biomolecules 2019; 9:517. [PMID: 31546643 PMCID: PMC6843513 DOI: 10.3390/biom9100517] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 01/13/2023] Open
Abstract
Alcoholic steatosis, characterized by an accumulation of triglycerides in hepatocytes, is one of the earliest pathological changes in the progression of alcoholic liver disease. In our previous study, we showed that alcohol-induced increase in serum ghrelin levels impair insulin secretion from pancreatic β-cells. The consequent reduction in the circulating insulin levels promote adipose-derived fatty acid mobilization to ultimately contribute to hepatic steatosis. In this study, we determined whether inhibition of ghrelin activity in chronic alcohol-fed rats could improve hepatic lipid homeostasis at the pancreas-adipose-liver axis. Adult Wistar rats were fed Lieber-DeCarli control or an ethanol liquid diet for 7 weeks. At 6 weeks, a subset of rats in each group were injected with either saline or ghrelin receptor antagonist, [d-Lys-3] GHRP-6 (DLys; 9 mg/kg body weight) for 5 days and all rats were sacrificed 2 days later. DLys treatment of ethanol rats improved pancreatic insulin secretion, normalized serum insulin levels, and the adipose lipid metabolism, as evidenced by the decreased serum free fatty acids (FFA). DLys treatment of ethanol rats also significantly decreased the circulating FFA uptake, de novo hepatic fatty acid synthesis ultimately attenuating alcoholic steatosis. To summarize, inhibition of ghrelin activity reduced alcoholic steatosis by improving insulin secretion, normalizing serum insulin levels, inhibiting adipose lipolysis, and preventing fatty acid uptake and synthesis in the liver. Our studies provided new insights on the important role of ghrelin in modulating the pancreas-adipose-liver, and promoting adipocyte lipolysis and hepatic steatosis. The findings offer a therapeutic approach of not only preventing alcoholic liver injury but also treating it.
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Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Jacy L Kubik
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
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27
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Fonseca TL, Fernandes GW, Bocco BMLC, Keshavarzian A, Jakate S, Donohue TM, Gereben B, Bianco AC. Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis. Alcohol Clin Exp Res 2019; 43:1376-1383. [PMID: 30908637 PMCID: PMC6602874 DOI: 10.1111/acer.14027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein. METHODS Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. RESULTS The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH. CONCLUSIONS EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.
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Affiliation(s)
- Tatiana L. Fonseca
- Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
| | - Gustavo W. Fernandes
- Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
| | | | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Rush University, Chicago IL
| | | | - Terrence M. Donohue
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha NE
| | - Balázs Gereben
- Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Antonio C. Bianco
- Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
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28
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Yang L, Yang C, Thomes PG, Kharbanda KK, Casey CA, McNiven MA, Donohue TM. Lipophagy and Alcohol-Induced Fatty Liver. Front Pharmacol 2019; 10:495. [PMID: 31143122 PMCID: PMC6521574 DOI: 10.3389/fphar.2019.00495] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the "first hit" in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs.
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Affiliation(s)
- Li Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Paul G. Thomes
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and 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
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A. Casey
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Mark A. McNiven
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, United States
| | - Terrence M. Donohue
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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29
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Rasineni K, Thomes PG, Kubik JL, Harris EN, Kharbanda KK, Casey CA. Chronic alcohol exposure alters circulating insulin and ghrelin levels: role of ghrelin in hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G453-G461. [PMID: 30702902 PMCID: PMC6483023 DOI: 10.1152/ajpgi.00334.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/07/2019] [Accepted: 01/16/2019] [Indexed: 01/31/2023]
Abstract
Fatty liver is the earliest response of the liver to excessive ethanol consumption. Central in the development of alcoholic steatosis is increased mobilization of nonesterified free fatty acids (NEFAs) to the liver from the adipose tissue. In this study, we hypothesized that ethanol-induced increase in ghrelin by impairing insulin secretion, could be responsible for the altered lipid metabolism observed in adipose and liver tissue. Male Wistar rats were fed for 5-8 wk with control or ethanol Lieber-DeCarli diet, followed by biochemical analyses in serum and liver tissues. In addition, in vitro studies were conducted on pancreatic islets isolated from experimental rats. We found that ethanol increased serum ghrelin and decreased serum insulin levels in both fed and fasting conditions. These results were corroborated by our observations of a significant accumulation of insulin in pancreatic islets of ethanol-fed rats, indicating that its secretion was impaired. Furthermore, ethanol-induced reduction in circulating insulin was associated with lower adipose weight and increased NEFA levels observed in these rats. Additionally, we found that increased concentration of serum ghrelin was due to increased synthesis and maturation in the stomach of the ethanol-fed rats. We also report that in addition to its effect on the pancreas, ghrelin can also directly act on hepatocytes via the ghrelin receptors and promote fat accumulation. In conclusion, alcohol-induced elevation of circulating ghrelin levels impairs insulin secretion. Consequently, reduced circulating insulin levels likely contribute to increased free fatty acid mobilization from adipose tissue to liver, thereby contributing to hepatic steatosis. NEW & NOTEWORTHY Our studies are the first to report that ethanol-induced increases in ghrelin contribute to impaired insulin secretion, which results in the altered lipid metabolism observed in adipose and liver tissue in the setting of alcoholic fatty liver disease.
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Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Paul G Thomes
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Jacy L Kubik
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska-Lincoln , Lincoln, Nebraska
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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30
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You M, Jogasuria A, Lee K, Wu J, Zhang Y, Lee YK, Sadana P. Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1. Curr Mol Pharmacol 2019; 10:226-236. [PMID: 26278388 DOI: 10.2174/1874467208666150817112109] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 08/07/2015] [Accepted: 08/07/2015] [Indexed: 02/06/2023]
Abstract
Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), is a bi-functional molecule involved in various signaling pathways via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional co-regulator. In the liver, lipin-1 is known to play a vital role in controlling the lipid metabolism and inflammation process at multiple regulatory levels. Alcoholic fatty liver disease (AFLD) is one of the earliest forms of liver injury and approximately 8-20% of patients with simple steatosis can develop into more severe forms of liver injury, including steatohepatitis, fibrosis/ cirrhosis, and eventually hepatocellular carcinoma (HCC). The signal transduction mechanisms for alcohol-induced detrimental effects in liver involves alteration of complex and multiple signaling pathways largely governed by a central and upstream signaling system, namely, sirtuin 1 (SIRT1)-AMP activated kinase (AMPK) axis. Emerging evidence suggests a pivotal role of lipin-1 as a crucial downstream regulator of SIRT1-AMPK signaling system that is likely to be ultimately responsible for development and progression of AFLD. Several lines of evidence demonstrate that ethanol exposure significantly induces lipin-1 gene and protein expression levels in cultured hepatocytes and in the livers of rodents, induces lipin-1-PAP activity, impairs the functional activity of nuclear lipin-1, disrupts lipin-1 mRNA alternative splicing and induces lipin-1 nucleocytoplasmic shuttling. Such impairment in response to ethanol leads to derangement of hepatic lipid metabolism, and excessive production of inflammatory cytokines in the livers of the rodents and human alcoholics. This review summarizes current knowledge about the role of lipin-1 in the pathogenesis of AFLD and its potential signal transduction mechanisms.
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Affiliation(s)
- Min You
- 4209 State Route 44, Rootstown OH 44272. United States
| | | | | | - Jiashin Wu
- Department of Pharmaceutical Sciences. 0
| | - Yanqiao Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States
| | - Yoon Kwang Lee
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States
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31
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Listenberger L, Townsend E, Rickertsen C, Hains A, Brown E, Inwards EG, Stoeckman AK, Matis MP, Sampathkumar RS, Osna NA, Kharbanda KK. Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis. Cells 2018; 7:230. [PMID: 30477200 PMCID: PMC6316228 DOI: 10.3390/cells7120230] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/19/2018] [Accepted: 11/22/2018] [Indexed: 02/05/2023] Open
Abstract
Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases in hepatic triglyceride mass, along with increases in LD number and size. Additionally, hepatic LDs from rats with early alcoholic liver injury show a decreased ratio of surface phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This occurred in parallel with an increase in the LD association of perilipin 2, a prominent LD protein. To determine if changes to the LD phospholipid composition contributed to differences in protein association with LDs, we constructed liposomes that modeled the LD PC:PE ratios in AFLD and control rats. Reducing the ratio of PC to PE increased the binding of perilipin 2 to liposomes in an in vitro experiment. Moreover, we decreased the ratio of LD PC:PE in NIH 3T3 and AML12 cells by culturing these cells in choline-deficient media. We again detected increased association of specific LD proteins, including perilipin 2. Taken together, our experiments suggest an important link between LD phospholipids, protein composition, and lipid accumulation.
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Affiliation(s)
- Laura Listenberger
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA.
| | - Elizabeth Townsend
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA.
| | - Cassandra Rickertsen
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA.
| | - Anastasia Hains
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA.
| | - Elizabeth Brown
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA.
| | - Emily G Inwards
- Department of Chemistry, Bethel University, St. Paul, MN 55112, USA.
| | | | - Mitchell P Matis
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE and Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Rebecca S Sampathkumar
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE and Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Natalia A Osna
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE and Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Kusum K Kharbanda
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE and Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
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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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Kharbanda KK, Ronis MJJ, Shearn CT, Petersen DR, Zakhari S, Warner DR, Feldstein AE, McClain CJ, Kirpich IA. Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress. Biomolecules 2018; 8:16. [PMID: 29587455 PMCID: PMC6022870 DOI: 10.3390/biom8020016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023] Open
Abstract
The symposium, "Role of Nutrition in Alcoholic Liver Disease", was held at the European Society for Biomedical Research on Alcoholism Congress on 9 October 2017 in Crete, Greece. The goal of the symposium was to highlight recent advances and developments in the field of alcohol and nutrition. The symposium was focused on experimental and clinical aspects in relation to the role of different types of dietary nutrients and malnutrition in the pathogenesis of alcoholic liver disease (ALD). The following is a summary of key research presented at this session. The speakers discussed the role of dietary fats and carbohydrates in the development and progression of alcohol-induced multi-organ pathology in animal models of ALD, analyzed novel nutrition-related therapeutics (specifically, betaine and zinc) in the treatment of ALD, and addressed clinical relevance of malnutrition and nutrition support in ALD. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows.
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Affiliation(s)
- Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Martin J J Ronis
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA.
| | - Dennis R Petersen
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA.
| | - Samir Zakhari
- Distilled Spirits Council, Washington, DC 20005, USA.
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
| | - Ariel E Feldstein
- Division of Gastroenterology, Department of Pediatrics, University of California, San Diego, CA 92037, USA.
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 402202, USA;.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Robley Rex Veterans Medical Center, Louisville, KY 40202, USA.
- Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 402202, USA.
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 402202, USA;.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 402202, USA.
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Ding L, Wo L, Du Z, Tang L, Song Z, Dou X. Danshen protects against early-stage alcoholic liver disease in mice via inducing PPARα activation and subsequent 4-HNE degradation. PLoS One 2017; 12:e0186357. [PMID: 29020055 PMCID: PMC5636149 DOI: 10.1371/journal.pone.0186357] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/30/2017] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is a type of chronic liver disease caused by long-term heavy ethanol consumption. Danshen is one of the most commonly used substances in traditional Chinese medicine and has been widely used for the treatment of various diseases, and most frequently, the ALD. The current study aims to determine the potential beneficial effect of Danshen administration on ALD and to clarify the underlying molecular mechanisms. Danshen administration improved liver pathologies of ALD, attenuated alcohol-induced increment of hepatic 4-Hydroxynonenal (4-HNE) formation, and prevented hepatic Peroxisome proliferators activated receptor alpha (PPARα) suppression in response to chronic alcohol consumption. Cell culture studies revealed that both hepatoprotective effect and increased intracellular 4-HNE clearance instigated by Danshen supplementation are PPARα-dependent. In conclusion, Danshen administration can protect against ALD via inducing PPARα activation and subsequent 4-HNE degradation.
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Affiliation(s)
- Lei Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Like Wo
- Zhejiang Provincial Hospital of Traditional Chinese Medical, Hangzhou, P. R. China
| | - Zhongyan Du
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Lihua Tang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Xiaobing Dou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
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Hepatic metabolic effects of Curcuma longa extract supplement in high-fructose and saturated fat fed rats. Sci Rep 2017; 7:5880. [PMID: 28724959 PMCID: PMC5517472 DOI: 10.1038/s41598-017-06220-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/08/2017] [Indexed: 12/11/2022] Open
Abstract
The metabolic effects of an oral supplementation with a Curcuma longa extract, at a dose nutritionally relevant with common human use, on hepatic metabolism in rats fed a high fructose and saturated fatty acid (HFS) diet was evaluated. High-resolution magic-angle spinning NMR and GC/MS in combination with multivariate analysis have been employed to characterize the NMR metabolite profiles and fatty acid composition of liver tissue respectively. The results showed a clear discrimination between HFS groups and controls involving metabolites such as glucose, glycogen, amino acids, acetate, choline, lysophosphatidylcholine, phosphatidylethanolamine, and β-hydroxybutyrate as well as an increase of MUFAs and a decrease of n-6 and n-3 PUFAs. Although the administration of CL did not counteract deleterious effects of the HFS diet, some metabolites, namely some n-6 PUFA and n-3 PUFA, and betaine were found to increase significantly in liver samples from rats having received extract of curcuma compared to those fed the HFS diet alone. This result suggests that curcuminoids may affect the transmethylation pathway and/or osmotic regulation. CL extract supplementation in rats appears to increase some of the natural defences preventing the development of fatty liver by acting on the choline metabolism to increase fat export from the liver.
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Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol 2017; 234:R1-R21. [PMID: 28428362 DOI: 10.1530/joe-16-0513] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 04/20/2017] [Indexed: 12/11/2022]
Abstract
Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.
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Affiliation(s)
- Caroline E Geisler
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
| | - Benjamin J Renquist
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
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Kocic G, Tomovic K, Kocic H, Sokolovic D, Djordjevic B, Stojanovic S, Arsic I, Smelcerovic A. Antioxidative, membrane protective and antiapoptotic effects of melatonin, in silico study of physico-chemical profile and efficiency of nanoliposome delivery compared to betaine. RSC Adv 2017. [DOI: 10.1039/c6ra24741e] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hepatoprotective effects of melatonin mediated by the inhibition of apoptotic and oxidative processes and activation of survival pathways, in comparison with betaine, were studied in mouse hepatocytes undergone Fas-ligand apoptosis.
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Affiliation(s)
- Gordana Kocic
- Institute of Biochemistry
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
| | - Katarina Tomovic
- Department of Pharmacy
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
| | - Hristina Kocic
- Faculty of Medicine
- University of Maribor
- Maribor 2000
- Slovenia
| | - Dusan Sokolovic
- Institute of Biochemistry
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
| | - Branka Djordjevic
- Institute of Biochemistry
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
| | - Svetlana Stojanovic
- Institute of Biochemistry
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
| | - Ivana Arsic
- Department of Pharmacy
- Faculty of Medicine
- University of Nis
- 18000 Nis
- Serbia
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Natarajan SK, Rasineni K, Ganesan M, Feng D, McVicker BL, McNiven MA, Osna NA, Mott JL, Casey CA, Kharbanda KK. Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease. Curr Mol Pharmacol 2017; 10:237-248. [PMID: 26278390 PMCID: PMC4820363 DOI: 10.2174/1874467208666150817111727] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 08/07/2015] [Accepted: 08/07/2015] [Indexed: 02/08/2023]
Abstract
For more than 30 years, lipid droplets (LDs) were considered as an inert bag of lipid for storage of energy-rich fat molecules. Following a paradigm shift almost a decade ago, LDs are presently considered an active subcellular organelle especially designed for assembling, storing and subsequently supplying lipids for generating energy and membrane synthesis (and in the case of hepatocytes for VLDL secretion). LDs also play a central role in many other cellular functions such as viral assembly and protein degradation. Here, we have explored the structural and functional changes that occur in hepatic and adipose tissue LDs following chronic ethanol consumption in relation to their role in the pathogenesis of alcoholic liver injury.
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Affiliation(s)
- Sathish Kumar Natarajan
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center
| | - Karuna Rasineni
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Murali Ganesan
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Dan Feng
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Benita L. McVicker
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Natalia A. Osna
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Justin L. Mott
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center
| | - Carol A. Casey
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center
| | - Kusum K. Kharbanda
- Research Service, VA Nebraska-Western Iowa Health Care System (VA NWIHCS), and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center
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Osna NA, Donohue TM, Kharbanda KK. Alcoholic Liver Disease: Pathogenesis and Current Management. Alcohol Res 2017; 38:147-161. [PMID: 28988570 PMCID: PMC5513682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.
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Affiliation(s)
- Natalia A Osna
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Terrence M Donohue
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Kusum K Kharbanda
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
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Krishnasamy Y, Ramshesh VK, Gooz M, Schnellmann RG, Lemasters JJ, Zhong Z. Ethanol and High Cholesterol Diet Causes Severe Steatohepatitis and Early Liver Fibrosis in Mice. PLoS One 2016; 11:e0163342. [PMID: 27676640 PMCID: PMC5038945 DOI: 10.1371/journal.pone.0163342] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/07/2016] [Indexed: 12/15/2022] Open
Abstract
Background and Aim Because ethanol consumption is commonly associated with a high cholesterol diet, we examined whether combined consumption of ethanol and high cholesterol increases liver injury and fibrosis. Methods Male C57BL/6J mice were fed diets containing: 1) 35% of calories from corn oil (CTR), 2) CTR plus 0.5% (w/v) cholesterol (Chol), 3) CTR plus ethanol (27% of calories) (EtOH), or 4) EtOH+Chol for 3 months. Results In mice fed Chol or EtOH alone, ALT increased to ~160 U/L, moderate hepatic steatosis occurred, and leukocyte infiltration, necrosis, and apoptosis increased modestly, but no observable fibrosis developed. By contrast in mice fed EtOH+Chol, ALT increased to ~270 U/L, steatosis was more extensive and mostly macrovesicular, and expression of proinflammatory molecules (HMGB-1, TLR4, TNFα, ICAM-1) and leukocyte infiltration increased substantially. Necrosis and apoptosis also increased. Trichrome staining and second harmonic generation microscopy revealed hepatic fibrosis. Fibrosis was mostly sinusoidal and/or perivenular, but in some mice bridging fibrosis occurred. Expression of smooth muscle α-actin and TGF-β1 increased slightly by Chol, moderately by EtOH, and markedly by EtOH+Chol. TGF-β pseudoreceptor BAMBI increased slightly by Chol, remained unchanged by EtOH and decreased by EtOH+Chol. MicroRNA-33a, which enhances TGF-β fibrotic effects, and phospho-Smad2/3, the down-stream signal of TGF-β, also increased more greatly by EtOH+Chol than Chol or EtOH. Metalloproteinase-2 and -9 were decreased only by EtOH+Chol. Conclusion High dietary cholesterol and chronic ethanol consumption synergistically increase liver injury, inflammation, and profibrotic responses and suppress antifibrotic responses, leading to severe steatohepatitis and early fibrosis in mice.
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Affiliation(s)
- Yasodha Krishnasamy
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Venkat K. Ramshesh
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Monika Gooz
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Rick G. Schnellmann
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America
| | - John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Institute of Theoretical & Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation
| | - Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
- * E-mail:
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Abstract
OBJECTIVES To explore the effect of betaine on alcoholic pancreatic steatosis and its mechanism. METHODS Rats were randomly assigned to control, ethanol, or ethanol + betaine groups. Changes in pancreatic morphology; serum lipid levels; and pancreatic lipid, amylase and lipase levels were determined. The serum and adipose tissue adiponectin level was measured by an enzyme-linked immunoassay. Adiponectin receptor-1 (AdipoR1), AdipoR2, sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, and fatty acid synthetase expression levels were quantified. The SREBP-1c expression in SW1990 cells treated with various concentrations of ethanol or ethanol plus betaine and/or adiponectin was assessed. RESULTS Alcohol-induced changes in pancreatic morphology were attenuated by betaine. Pancreatic triglyceride, free fatty acid and expression levels of SREBP-1c and fatty acid synthetase were elevated after ethanol feeding but remained at control levels after betaine supplementation. Alcohol-induced decreases in serum and adipose tissue adiponectin, pancreatic AdipoR1, amylase, and lipase were attenuated by betaine. Serum triglyceride and free fatty acid levels were elevated after alcohol consumption and remained higher after betaine supplementation compared with controls. Betaine and/or adiponectin suppressed alcohol-induced SREBP-1c upregulation in vitro. CONCLUSIONS Betaine attenuated alcoholic-induced pancreatic steatosis most likely by suppressing pancreatic SREBP-1c both directly and through the restoration of adiponectin signaling.
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Natarajan SK, Pachunka JM, Mott JL. Role of microRNAs in Alcohol-Induced Multi-Organ Injury. Biomolecules 2015; 5:3309-38. [PMID: 26610589 PMCID: PMC4693280 DOI: 10.3390/biom5043309] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 11/16/2015] [Indexed: 12/12/2022] Open
Abstract
Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, alcoholic cardiomyopathy, and muscle damage. Further, we have reviewed the role of altered microRNAs in the circulation, teratogenic effects of alcohol, and during maternal or paternal alcohol consumption.
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Affiliation(s)
- Sathish Kumar Natarajan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Joseph M Pachunka
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Justin L Mott
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA.
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Ganesan M, Zhang J, Bronich T, Poluektova LI, Donohue TM, Tuma DJ, Kharbanda KK, Osna NA. Acetaldehyde accelerates HCV-induced impairment of innate immunity by suppressing methylation reactions in liver cells. Am J Physiol Gastrointest Liver Physiol 2015; 309:G566-G577. [PMID: 26251470 PMCID: PMC6842870 DOI: 10.1152/ajpgi.00183.2015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/04/2015] [Indexed: 02/08/2023]
Abstract
Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective antiviral genes is induced by IFN-α signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFN-α signaling modulation are not well elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFN-α signaling in liver cells via impairment of methylation reactions. HCV-infected Huh7.5 CYP2E1(+) cells and human hepatocytes were exposed to acetaldehyde (Ach)-generating system (AGS) and stimulated with IFN-α to activate IFN-sensitive genes (ISG) via the Jak-STAT-1 pathway. We observed significant suppression of signaling events by Ach. Ach exposure decreased STAT-1 methylation via activation of protein phosphatase 2A and increased the protein inhibitor of activated STAT-1 (PIAS-1)-STAT-1 complex formation in both HCV(+) and HCV(-) cells, preventing ISG activation. Treatment with a promethylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism-induced changes in ISGs are methylation related and confirmed by in vivo studies on HCV(+) transgenic mice. HCV- and Ach-induced impairment of IFN signaling temporarily increased HCV RNA levels followed by apoptosis of heavily infected cells. We concluded that Ach potentiates the suppressive effects of HCV on activation of ISGs attributable to methylation-dependent dysregulation of IFN-α signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus can be used for treatment of HCV(+) alcohol-abusing patients.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Jinjin Zhang
- School of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
| | - Tatiana Bronich
- School of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
| | - Larisa I Poluektova
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Pharmacology and Experimental Neuroscience, Omaha, Nebraska
| | - Terrence M Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Dean J Tuma
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
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Ahn CW, Choi YJ, Hong SH, Jun DS, Na JD, Choi YJ, Kim YC. Involvement of multiple pathways in the protection of liver against high-fat diet-induced steatosis by betaine. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.05.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Thomes PG, Osna NA, Bligh SM, Tuma DJ, Kharbanda KK. Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity. Biochem Pharmacol 2015; 96:30-38. [PMID: 25931143 DOI: 10.1016/j.bcp.2015.04.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/23/2015] [Indexed: 02/05/2023]
Abstract
Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complex; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD.
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Affiliation(s)
- Paul G Thomes
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; 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; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sarah M Bligh
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Dean J Tuma
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; 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; 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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Deminice R, da Silva RP, Lamarre SG, Kelly KB, Jacobs RL, Brosnan ME, Brosnan JT. Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism. Amino Acids 2015; 47:839-46. [DOI: 10.1007/s00726-014-1913-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 12/30/2014] [Indexed: 02/07/2023]
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Influence of fat/carbohydrate ratio on progression of fatty liver disease and on development of osteopenia in male rats fed alcohol via total enteral nutrition (TEN). Alcohol 2014; 48:133-44. [PMID: 24581955 DOI: 10.1016/j.alcohol.2013.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 12/04/2013] [Accepted: 12/16/2013] [Indexed: 12/12/2022]
Abstract
Alcohol abuse is associated with the development of fatty liver disease and also with significant osteopenia in both genders. In this study, we examined ethanol-induced pathology in response to diets with differing fat/carbohydrate ratios. Male Sprague-Dawley rats were fed intragastrically with isocaloric liquid diets. Dietary fat content was either 5% (high carbohydrate, HC) or 45% (high fat, HF), with or without ethanol (12-13 g/kg/day). After 14, 28, or 65 days, livers were harvested and analyzed. In addition, bone morphology was analyzed after 65 days. HC rats gained more weight and had larger fat pads than HF rats with or without ethanol. Steatosis developed in HC + ethanol (HC + EtOH) compared to HF + ethanol (HF + EtOH) rats, accompanied by increased fatty acid (FA) synthesis and increased nuclear carbohydrate response element binding protein (ChREBP) (p < 0.05), but in the absence of effects on hepatic silent mating type information regulation 2 homolog (SIRT-1) or nuclear sterol regulatory binding element protein (SREBP-1c). Ethanol reduced serum leptin (p < 0.05) but not adiponectin. Over time, HC rats developed fatty liver independent of ethanol. FA degradation was significantly elevated by ethanol in both HC and HF groups (p < 0.05). HF + EtOH rats had increased oxidative stress from 28 days, increased necrosis compared to HF controls and higher expression of cytochromes P450, CYP2E1, and CYP4A1 compared to HC + EtOH rats (p < 0.05). In contrast, HC + EtOH rats had no significant increase in oxidative stress until day 65 with no observed increase in necrosis. Unlike liver pathology, no dietary differences were observed on ethanol-induced osteopenia in HC compared to HF groups. These data demonstrate that interactions between diet composition and alcohol are complex, dependent on the length of exposure, and are an important influence in development of fatty liver injury. Importantly, it appears that diet composition does not affect alcohol-associated skeletal toxicity.
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Hu M, Yin H, Mitra MS, Liang X, Ajmo JM, Nadra K, Chrast R, Finck BN, You M. Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice. Hepatology 2013; 58:1953-63. [PMID: 23787969 PMCID: PMC3835749 DOI: 10.1002/hep.26589] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 06/12/2013] [Indexed: 12/22/2022]
Abstract
UNLABELLED Lipin-1 regulates lipid metabolism by way of its function as an enzyme in the triglyceride synthesis pathway and as a transcriptional coregulatory protein and is highly up-regulated in alcoholic fatty liver disease. In the present study, using a liver-specific lipin-1-deficient (lipin-1LKO) mouse model, we aimed to investigate the functional role of lipin-1 in the development of alcoholic steatohepatitis and explore the underlying mechanisms. Alcoholic liver injury was achieved by pair feeding wild-type and lipin-1LKO mice with modified Lieber-DeCarli ethanol-containing low-fat diets for 4 weeks. Surprisingly, chronically ethanol-fed lipin-1LKO mice showed markedly greater hepatic triglyceride and cholesterol accumulation, and augmented elevation of serum liver enzymes accompanied by increased hepatic proinflammatory cytokine expression. Our studies further revealed that hepatic removal of lipin-1 in mice augmented ethanol-induced impairment of hepatic fatty acid oxidation and lipoprotein production, likely by way of deactivation of peroxisome proliferator-activated receptor γ coactivator-1 alpha, a prominent transcriptional regulator of lipid metabolism. CONCLUSIONS Liver-specific lipin-1 deficiency in mice exacerbates the development and progression of experimental alcohol-induced steatohepatitis. Pharmacological or nutritional modulation of hepatic lipin-1 may be beneficial for the prevention or treatment of human alcoholic fatty liver disease.
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Affiliation(s)
- Ming Hu
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Huquan Yin
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Mayurranjan S. Mitra
- Department of Medicine, Washington University School of Medicine, St.Louis, MO 63110, USA
| | - Xiaomei Liang
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Joanne M. Ajmo
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Karim Nadra
- Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland
| | - Roman Chrast
- Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland
| | - Brian N. Finck
- Department of Medicine, Washington University School of Medicine, St.Louis, MO 63110, USA
| | - Min You
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
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McRae MP. Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. J Chiropr Med 2013; 12:20-5. [PMID: 23997720 DOI: 10.1016/j.jcm.2012.11.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 11/17/2012] [Accepted: 11/30/2012] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Betaine supplementation has been shown to be an effective agent for decreasing plasma homocysteine in healthy adults. Studies in healthy volunteers show that 6 g/d of betaine lowers plasma homocysteine concentrations by 5% to 20%. The purpose of this study was to perform a meta-analysis of randomized placebo-controlled trials that used daily betaine supplementation to identify the range in betaine's effects on lowering homocysteine. METHODS Five randomized controlled trials published between 2002 and 2010 were identified using MEDLINE and a manual search. All 5 studies used health adult participants who were supplemented with at least 4 g/d of betaine for between 6 and 24 weeks. A meta-analysis was carried out using a random-effects model, and the overall effect size was calculated for changes in plasma homocysteine. RESULTS The pooled estimate of effect for betaine supplementation on plasma homocysteine was a reduction of 1.23 μmol/L, which was statistically significant (95% confidence interval, - 1.61 to - 0.85; P = .01). CONCLUSION Supplementation with at least 4g/d of betaine for a minimum of 6 weeks can lower plasma homocysteine.
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Affiliation(s)
- Marc P McRae
- Associate Professor, Department of Basic Science, National University of Health Sciences, Lombard, IL
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Betaine attenuates lysophosphatidylcholine-mediated adhesion molecules in aged rat aorta: modulation of the nuclear factor-κB pathway. Exp Gerontol 2013; 48:517-24. [PMID: 23466300 DOI: 10.1016/j.exger.2013.02.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 01/31/2013] [Accepted: 02/25/2013] [Indexed: 01/18/2023]
Abstract
We previously reported that lysophosphatidylcholine (LPC) is a mediator of endothelial dysfunction in the expression of adhesion molecules (AMs) during aging. This study aimed at investigating the effects of betaine on LPC-related expression of AMs and the molecular modulation of nuclear factor-κB (NF-κB) activation in the aorta of aged rats and rat endothelial YPEN-1 cells. The experiment was performed on young (7 months) and old (21 months) rats; 2 groups of old rats were fed betaine (3 or 6 mg · kg(-1) · day(-1) for 10 days). Betaine inhibited the expression of LPC-related AMs in the serum and tissue of aged rats, without affecting the elevated levels of serum LPC. Betaine also prevented the generation of reactive species, thereby maintaining the redox status via the enhancement of the thiol status during aging. Furthermore, betaine attenuated NF-κB activation via the dephosphorylation of IκB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged aorta and LPC-treated YPEN-1 cells. Thus, betaine suppressed the LPC-related AM expression associated with NF-κB activation via the upregulation of IKK/MAPKs. Our findings provide insights into the prevention of vascular disorders and the development of interventions based on natural compounds, such as betaine.
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