The Synergistic and Opposing Roles of ω-Fatty Acid Hydroxylase (CYP4A11) and ω-1 Fatty Acid Hydroxylase (CYP2E1) in Chronic Liver Disease.

Abstract

Cytochrome P450 fatty acid hydroxylase consists of members of the CYP4 family that ω-hydroxylate fatty acids and the CYP2E1 that ω-1 hydroxylates fatty acids. Although ω and ω-1 hydroxylation of fatty acids have been thought to play a minor role in fatty acid metabolism (less than 20%), it plays a vital role in excess liver fatty acids overload seen in fasting, diabetes, metabolic disorder, and over-consumption of alcohol and high-fat diet. This pathway provides anabolic metabolites for gluconeogenesis, succinate, and acetate for lipogenesis. The CYP4A and CYP2E1 genes are activated in fasting and several metabolic disorders, suggesting a synergistic role in preventing fatty acid-induced lipotoxicity with the consequence of increased liver cholesterol and lipogenesis leading to increased Lipid Droplet (LD) deposition. During the progression of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), activation of Phospholipase A2 (PLA₂) releases arachidonic acid that CYP4A11 and CYP2E1 P450s metabolize to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and 19-HETE, respectively. These metabolites have opposing roles in the progression of MASLD and chronic liver disease (CLD). This report discusses the synergistic role of the CYP4A and CYP2E1 P450s in the metabolism of saturated and unsaturated fatty acids and their opposite physiological role in the metabolism of Arachidonic Acid (AA). We finally discuss the role of ethanol in disrupting the synergistic and opposing roles of the CYP4A and CYP2E1 genes in MASLD and CLD.