CYP450 network shifts in MASLD/MASH: from pathogenesis to nutrition-informed modulation

Area of Science:

• Hepatology and Nutritional Science
• Drug Metabolism and Xenobiotic Interactions
• Molecular and Cellular Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are rising health concerns linked to obesity and poor diet.
• Cytochrome P450 (CYP450) enzymes are critical for drug metabolism, lipid handling, and responding to nutritional and environmental exposures, but their role in MASLD/MASH is not fully understood from a nutritional perspective.

Purpose of the Study:

• To review and integrate the current understanding of how diet-related exposures influence hepatic CYP450 pathways in the context of MASLD/MASH.
• To map the relationships between dietary patterns, food contaminants, and bioactive compounds with CYP450 function in the metabolically compromised liver.

Main Methods:

• A qualitative framework was used to review existing literature on nutrition-exposure-CYP relationships in MASLD/MASH.
• Evidence from human tissue studies, animal models, in vitro experiments, and mechanistic studies was integrated.

Main Results:

• Obesity, high-fat diets, fructose, and specific fatty acid compositions can alter hepatic CYP450 activity and expression, particularly CYP3A4, in MASLD/NASH.
• Metabolic inflammation appears to promote pro-oxidant CYP pathways (e.g., CYP2E1) while potentially impairing detoxification pathways (e.g., CYP3A).
• Food contaminants like nitrosamines and aflatoxin B1 may undergo CYP-dependent bioactivation, though human validation in MASLD/MASH is limited.

Conclusions:

• Nutrition-related remodeling of CYP450 enzymes is a key interface linking diet, oxidative stress, xenobiotic handling, and MASLD/MASH progression.
• Future research should combine dietary assessments with CYP activity measures, oxidative stress biomarkers, and gut-liver axis markers for a comprehensive understanding.