ArticleAlcoholism, clinical and experimental research2022
Cytochrome P450 2E1-dependent hepatic ethanol metabolism induces fatty acid-binding protein 4 and steatosis.
Article in Alcoholism, clinical and experimental research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 12 citations in OpenAlex.
- [Histone deacetylases and alcohol-related liver disease].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- SIRT1-mediated FABP4 destabilization attenuates fibrosis and ferroptosis in non-alcoholic fatty liver disease.Clinical and experimental medicine · 2026Article
- Mechanism Study on the Regulation of Intestinal Microecology by Hangover Liver-Protecting Beverage for the Treatment of Alcoholic Liver Disease.Food science & nutrition · 2026Article
- Acute Acetaminophen Hepatotoxicity And Platelet Dysfunction.Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2025Article
- FABP4 deficiency ameliorates alcoholic steatohepatitis in mice via inhibition of p53 signaling pathway.Scientific reports · 2024Article
- Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.Biomolecules · 2024Review
- A Review: Cytochrome P450 in Alcoholic and Non-Alcoholic Fatty Liver Disease.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- The Synergistic and Opposing Roles of ω-Fatty Acid Hydroxylase (Genome biology & molecular genetics · 2024Article
- Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism.Biology · 2022Article
- Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's mouse model.Frontiers in neuroscience · 2022Article
- Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes.Frontiers in pharmacology · 2022Review
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4 authors at 1 institution in 1 country.
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Abstract
backgroundHepatic steatosis is an early pathology of alcohol-associated liver disease (ALD). Fatty acid-binding protein-4 (FABP4, a FABP not normally produced in the liver) is secreted by hepatocytes in ALD and stimulates hepatoma proliferation and migration. This study sought to investigate the mechanism[s] by which hepatic ethanol metabolism regulates FABP4 and steatosis.
methodsHuman hepatoma cells (HepG2/HuH7) and cells stably transfected to express cytochrome P450 2E1 (CYP2E1), were exposed to ethanol in the absence or presence of chlormethiazole (a CYP2E1-inhibitor; CMZ) and/or EX-527 (a sirtuin-1 [SIRT1] inhibitor). The culture medium was analyzed for ethanol metabolism and FABP4 protein abundance. Cells were analyzed for FABP4 mRNA expression, SIRT1 protein abundance, and neutral lipid accumulation. In parallel, cells were analyzed for forkhead box O1 [FOXO1], β-catenin, peroxisome proliferator-activated receptor-α [PPARα], and lipin-1α protein abundance in the absence or presence of ethanol and pharmacological inhibitors of the respective target proteins.
resultsCYP2E1-dependent ethanol metabolism inhibited the amount of SIRT1 protein detected, concomitant with increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation, effects abolished by CMZ. Analysis of pathways associated with lipid oxidation revealed increased FOXO1 nuclear localization and decreased β-catenin, PPARα, and lipin-1α protein levels in CYP2E1-expressing cells in the presence of ethanol. Pharmacological inhibition of SIRT1 mimicked the effects of ethanol, while inhibition of FOXO1 abrogated the effect of ethanol on FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation in CYP2E1-expressing cells. Pharmacological inhibition of β-catenin, PPARα, or lipin-1α failed to alter the effects of ethanol on FABP4 or neutral lipid accumulation.
conclusionCYP2E1-dependent ethanol metabolism inhibits SIRT1-FOXO1 signaling, which leads to increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation. These data suggest that FABP4 released from steatotic hepatocytes could play a role in promoting tumor cell expansion in the setting of ALD and represents a potential target for therapeutic intervention.
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