Background And Aims: Alcoholic liver disease (ALD) represents a critical global health challenge characterized by liver damage resulting from excessive alcohol consumption. Early detection and timely intervention are essential for optimizing patient outcomes. However, the mechanisms underlying alcohol-induced liver injury have not been fully elucidated. Fibroblast growth factor 4 (FGF4) has been implicated in the progression of various liver diseases. This study aims to elucidate the role of FGF4 in the pathogenesis of ALD.
Approach And Results: We analyzed human liver specimens and observed significant upregulation of FGF4 mRNA and protein levels in patients with ALD. Consistent findings were noted in mouse models subjected to a Lieber-DeCarli liquid diet. Importantly, hepatic FGF4 expression exhibited a positively correlated with ALD severity in both human subjects and murine models. Hepatocyte-specific deletion of Fgf4 (Fgf4-LKO) exacerbated alcohol-induced liver injury through increased oxidative stress, inflammation, and apoptosis. Specifically, Fgf4-LKO mice demonstrated heightened susceptibility to ethanol plus CCl4-induced fibrosis and liver injury. However, treatment with the ERRγ inverse agonist GSK5182 and CYP2E1 inhibitor chlormethiazole (CMZ) mitigated the exacerbated liver injury associated with Fgf4 deficiency. Mechanistic investigations revealed that FGFR4 phosphorylates ERRγ, promoting its ubiquitination and degradation in hepatocytes. Hepatic-specific knockout of Fgfr4 intensified alcohol-induced liver injury and nullified the protective conferred of recombinant FGF4△NT.
Conclusions: Our study identifies FGF4 as a stress-responsive regulator in liver pathophysiology, operating via an FGFR4-mediated ERRγ-CYP2E1 signaling pathway. These results underscore the potential of FGF4 and its downstream pathways as therapeutic targets for ALD treatment.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/HEP.0000000000001282 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of N6-methyladenosine methylation of ASC by berberine ameliorates pyroptosis of renal tubular epithelial cells in acute kidney injury.
Cell Signal
March 2025
Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, PR China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University Zhengzhou, Henan, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of, China. Electronic address:
Acute kidney injury (AKI) lacks a definitive therapeutic approach beyond supportive care. One significant pathological mechanism involves the regulated death of tubular epithelial cells; however, the regulatory mechanisms underlying this cell death pathway require further investigation. The N6-methyladenosine (m6A) modification, recognized as the most prevalent modification in eukaryotes, plays a critical role in the regulatory processes associated with AKI.
View Article and Find Full Text PDFPotentially low-value operative care in abdominal trauma: A retrospective National Trauma Data Bank study.
Surgery
March 2025
Department of Social and Preventative Medicine, Université Laval, Québec, Québec, Canada; Population Health and Optimal Health Practices Research Unit, Trauma - Emergency - Critical Care Medicine, Centre de Recherche du CHU de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Québec, Québec, Canada. Electronic address:
Background: We currently lack national data on adherence to American College of Surgeons recommendations on nonoperative management for hemodynamically stable adults with solid-organ injuries. We aimed to estimate the incidence and interhospital variation in potentially low-value operative management for adults with blunt solid abdominal organ injuries.
Methods: We included adults with blunt solid-organ injury eligible for nonoperative management (grades I-IV spleen and liver and grade I-III kidney, hemodynamically stable on arrival, and no blood products used in the emergency department) who were admitted to trauma centers in the United States that submitted data to the National Trauma Data Bank between 2016 and 2019.
Study on the pharmacodynamic substances and mechanism of hepatoprotection of Acanthus ilicifolius Linn.
Phytomedicine
March 2025
Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province, Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 23788 Gongye North Road, Jinan 250100, PR China. Electronic address:
Background: The coastal wetland mangrove plant Acanthus ilicifolius l. (AI) is used as traditional medicine for liver protection and liver fibrosis treatment, but the pharmacodynamics of the hepatoprotective substance and the mechanisms of liver protection are not clear.
Purpose: This work aimed to assess the liver-protective ability of AI and elucidate the pharmacodynamics of the hepatoprotective substance of AI responsible for its liver activity.
Caveolin-1 protects against liver injury and lipid accumulation in alcoholic fatty liver via ferroptosis resistance.
Mol Immunol
March 2025
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Electronic address:
Alcoholic fatty liver (AFL) is one of the most common chronic liver diseases globally with complex and controversial pathogenesis. Recent evidence suggests that iron overload and lipid peroxidation are risk factors for AFL. Caveolin-1 (CAV1) is an important signal platform that can maintain lipid homeostasis during the development of non-alcoholic fatty liver.
View Article and Find Full Text PDFTianjihuang compound alleviates aflatoxin B-induced hepatic steatosis and fibrosis by targeting PPARα-TGF-β pathway in ducklings.
Poult Sci
March 2025
Department of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing 402460, PR China; Institute of Traditional Chinese Veterinary Medicine, Southwest University, Chongqing 402460, PR China; Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, PR China.
Aflatoxin B (AFB), a potent mycotoxin, poses a significant threat to the poultry industry, particularly affecting the health and growth of ducklings. The present study aimed to investigate the therapeutic effects and mechanisms of the Tianjihuang compound (HRS), a traditional Chinese medicine formulation, on AFB-induced chronic toxicity in ducklings. Firstly, 30 ingredients, including neochlorogenic acid, kaempferol 3-alpha-D-galactoside, quercetin, hispidulin, caffeic acid, and myricetin, were identified from HRS with UPLC-MS/MS method.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!