Constitutive androstane receptor, liver pathophysiology and chemical contaminants: current evidence and perspectives DOI Creative Commons
Francesca De Battistis, Aleksandra Buha Djordjević, Luciano Saso

et al.

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Introduction The Constitutive Androstane Receptor (CAR) (NR1I3), a pivotal member of the xenosensor family, plays key role in hepatic detoxification xenobiotic and endobiotic chemicals through induction expression drug-metabolizing enzymes transporters. CAR’s involvement extends beyond detoxification, influencing gluconeogenesis, lipogenesis, bile acid regulation, cellular processes such as proliferation, tissue regeneration, carcinogenesis. This review explores CAR regulation by various factors, highlighting its mediating metabolic changes induced environmental contaminants. Methods A literature search was conducted to identify all articles on PubMed website which CAR-contaminant CAR-hepatic steatosis relationship is analyzed both vitro vivo models. Results Numerous contaminants, perfluorooctanoic (PFOA), Zearalenone mycotoxin, PCB, triazole fungicide propiconazole can activate nuclear receptors contributing development increased de novo decreased fatty oxidation, lipid uptake, gluconeogenesis. Indirect activation pathways, particularly involving PFOA, are discussed context PPARα-independent mechanisms leading hepatotoxicity, including hepatocellular hypertrophy necrosis, their implications nonalcoholic steatohepatitis (NASH) liver disease (NAFLD). prevalence NAFLD, significant component syndrome, underscores importance understanding pathogenesis. Conclusions Experimental epidemiological data suggest that endocrine disruptors, especially pesticides, play NAFLD’s progression via CAR-regulated pathways. advocates for inclusion modern toxicological risk assessment tools, New Approach Methodologies (NAMs), Adverse Outcome Pathways (AOPs), Integrated Approaches Testing Assessment (IATA), elucidate CAR-mediated effects enhance regulatory frameworks.

Language: Английский

Constitutive androstane receptor, liver pathophysiology and chemical contaminants: current evidence and perspectives DOI Creative Commons
Francesca De Battistis, Aleksandra Buha Djordjević, Luciano Saso

et al.

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Introduction The Constitutive Androstane Receptor (CAR) (NR1I3), a pivotal member of the xenosensor family, plays key role in hepatic detoxification xenobiotic and endobiotic chemicals through induction expression drug-metabolizing enzymes transporters. CAR’s involvement extends beyond detoxification, influencing gluconeogenesis, lipogenesis, bile acid regulation, cellular processes such as proliferation, tissue regeneration, carcinogenesis. This review explores CAR regulation by various factors, highlighting its mediating metabolic changes induced environmental contaminants. Methods A literature search was conducted to identify all articles on PubMed website which CAR-contaminant CAR-hepatic steatosis relationship is analyzed both vitro vivo models. Results Numerous contaminants, perfluorooctanoic (PFOA), Zearalenone mycotoxin, PCB, triazole fungicide propiconazole can activate nuclear receptors contributing development increased de novo decreased fatty oxidation, lipid uptake, gluconeogenesis. Indirect activation pathways, particularly involving PFOA, are discussed context PPARα-independent mechanisms leading hepatotoxicity, including hepatocellular hypertrophy necrosis, their implications nonalcoholic steatohepatitis (NASH) liver disease (NAFLD). prevalence NAFLD, significant component syndrome, underscores importance understanding pathogenesis. Conclusions Experimental epidemiological data suggest that endocrine disruptors, especially pesticides, play NAFLD’s progression via CAR-regulated pathways. advocates for inclusion modern toxicological risk assessment tools, New Approach Methodologies (NAMs), Adverse Outcome Pathways (AOPs), Integrated Approaches Testing Assessment (IATA), elucidate CAR-mediated effects enhance regulatory frameworks.

Language: Английский

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