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Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease
Inseon Hwang, Jung Eun Nam, Wonsuk Choi, Won Gun Choi, Eunji Lee, Hyeongseok Kim, Young-Ah Moon, Jun Yong Park, Hail Kim
Received April 26, 2024  Accepted September 21, 2024  Published online February 5, 2025  
DOI: https://doi.org/10.4093/dmj.2024.0215    [Epub ahead of print]
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AbstractAbstract PDF
Background
Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood.
Methods
Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation.
Results
Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver- specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model.
Conclusion
GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD.
Reviews
Metabolic Risk/Epidemiology
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Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome
Scott L. Friedman
Diabetes Metab J. 2024;48(2):161-169.   Published online January 26, 2024
DOI: https://doi.org/10.4093/dmj.2023.0240
  • 5,795 View
  • 442 Download
  • 11 Crossref
AbstractAbstract PDFPubReader   ePub   
Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty liver disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The disease is typically a component of the metabolic syndrome that accompanies obesity, and is often overlooked because the liver manifestations are clinically silent until late-stage disease is present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have a higher fraction of patients who are lean, yet their illness has the same prognosis or worse than those who are obese. Nonetheless, ongoing injury can lead to hepatic inflammation and ballooning of hepatocytes as classic features. Over time, fibrosis develops following activation of hepatic stellate cells, the liver’s main fibrogenic cell type. The disease is usually more advanced in patients with type 2 diabetes mellitus, indicating that all diabetic patients should be screened for liver disease. Although there has been substantial progress in clarifying pathways of injury and fibrosis, there no approved therapies yet, but current research seeks to uncover the pathways driving hepatic inflammation and fibrosis, in hopes of identifying new therapeutic targets. Emerging molecular methods, especially single cell sequencing technologies, are revolutionizing our ability to clarify mechanisms underlying MASLD-associated fibrosis and HCC.

Citations

Citations to this article as recorded by  
  • The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment
    Eleni Michalopoulou, John Thymis, Stamatios Lampsas, George Pavlidis, Konstantinos Katogiannis, Dimitrios Vlachomitros, Eleni Katsanaki, Gavriella Kostelli, Sotirios Pililis, Loukia Pliouta, Aikaterini Kountouri, Ioannis S. Papanikolaou, Vaia Lambadiari,
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  • Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques
    Sergio Gil-Rojas, Miguel Suárez, Pablo Martínez-Blanco, Ana M. Torres, Natalia Martínez-García, Pilar Blasco, Miguel Torralba, Jorge Mateo
    Metabolites.2024; 14(6): 305.     CrossRef
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    Na Young Lee, Myeung Gi Choi, Eui Jin Lee, Ja Hyun Koo
    Archives of Pharmacal Research.2024; 47(6): 558.     CrossRef
  • New Biomarkers in Liver Fibrosis: A Pass through the Quicksand?
    Marzia Tagliaferro, Mariapaola Marino, Valerio Basile, Krizia Pocino, Gian Ludovico Rapaccini, Gabriele Ciasca, Umberto Basile, Valeria Carnazzo
    Journal of Personalized Medicine.2024; 14(8): 798.     CrossRef
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    Heliyon.2024; 10(19): e38339.     CrossRef
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    Daniela Gabbia
    Biology.2024; 13(10): 760.     CrossRef
  • Kisspeptin Alleviates Human Hepatic Fibrogenesis by Inhibiting TGFβ Signaling in Hepatic Stellate Cells
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    Cells.2024; 13(19): 1651.     CrossRef
  • Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders
    Michal Selc, Radka Macova, Andrea Babelova
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  • Valorizing Agro‐Food Waste for Nutraceutical Development: Sustainable Approaches for Managing Metabolic Dysfunction‐Associated Steatotic Liver Disease and Related Co‐Morbidities
    Laura Comi, Claudia Giglione, Fationa Tolaj Klinaku, Federico Pialorsi, Valentina Tollemeto, Maria Zurlo, Antonio Seneci, Paolo Magni
    Food Frontiers.2024;[Epub]     CrossRef
Clinical Diabetes & Therapeutics
Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment
Kyung-Soo Kim, Byung-Wan Lee, Yong Jin Kim, Dae Ho Lee, Bong-Soo Cha, Cheol-Young Park
Diabetes Metab J. 2019;43(2):127-143.   Published online April 15, 2019
DOI: https://doi.org/10.4093/dmj.2019.0034
  • 10,113 View
  • 182 Download
  • 29 Web of Science
  • 38 Crossref
AbstractAbstract PDFPubReader   

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders that are often comorbid conditions. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone; pharmacological treatments are helpful in this regard. Although many drugs have been investigated, pioglitazone could be a first-line therapy in patients with NAFLD and diabetes. Many more drugs are currently being developed and investigated, and it is likely that combination strategies will be used for future treatment of NAFLD and diabetes. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.

Citations

Citations to this article as recorded by  
  • The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment
    Eleni Michalopoulou, John Thymis, Stamatios Lampsas, George Pavlidis, Konstantinos Katogiannis, Dimitrios Vlachomitros, Eleni Katsanaki, Gavriella Kostelli, Sotirios Pililis, Loukia Pliouta, Aikaterini Kountouri, Ioannis S. Papanikolaou, Vaia Lambadiari,
    Journal of Clinical Medicine.2025; 14(2): 428.     CrossRef
  • Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study
    Kyung-Soo Kim, Sangmo Hong, Kyungdo Han, Cheol-Young Park
    BMJ.2024; : e076388.     CrossRef
  • The Efficacy of Empagliflozin in Combination with Pioglitazone on the Improvement of Fatty Liver Disease in Patients with Type 2 Diabetes
    Morteza Aghajanpoor, Mehrzad Gholampourdehaki, Reza Mosaed, Iraj Mirzaii-Dizgah, Afsaneh Vosughi
    Annals of Military and Health Sciences Research.2024;[Epub]     CrossRef
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    强江 郭
    Advances in Clinical Medicine.2024; 14(03): 561.     CrossRef
  • Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies
    Alhussain Yasin, Madison Nguyen, Angad Sidhu, Priyanka Majety, Jared Spitz, Amon Asgharpour, Mohammad S. Siddiqui, Laurence S. Sperling, Arshed A. Quyyumi, Anurag Mehta
    Diabetes Research and Clinical Practice.2024; 211: 111650.     CrossRef
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    Rizwana Parveen, Shadan Hussain, Sparsh Saini, Parvej Khan, Nilanjan Saha, Nidhi
    Expert Opinion on Pharmacotherapy.2024; 25(7): 925.     CrossRef
  • Effect of aerobic training with silymarin consumption on glycemic indices and liver enzymes in men with type 2 diabetes
    Keyvan Ghalandari, Mojtaba Shabani, Ali Khajehlandi, Amin Mohammadi
    Archives of Physiology and Biochemistry.2023; 129(1): 76.     CrossRef
  • Metabolic Dysfunction-Associated Fatty Liver Disease and Mortality: A Population-Based Cohort Study
    Kyung-Soo Kim, Sangmo Hong, Hong-Yup Ahn, Cheol-Young Park
    Diabetes & Metabolism Journal.2023; 47(2): 220.     CrossRef
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