Induction of Peroxisomal β-Oxidation as a Critical Mechanism for Ethanol-Induced Hepatic Triglyceride Accumulation

Excessive oxidation of ethanol has been well known to induce hepatic triglyceride accumulation, while the underlying pathogenic mechanisms are not fully demonstrated. The peroxisomal catalase–hydrogen peroxide complex system plays a role in the metabolism of ethanol, while the potential origin of hydrogen peroxide involved in ethanol oxidation by this system is not determined. As peroxisomal fatty acid β-oxidation generates hydrogen peroxide and can be induced under ketogenic conditions, we hypothesize that induction of peroxisomal β-oxidation might accelerate ethanol oxidation through increasing the supply of hydrogen peroxide. The study reveals a novel mechanism by which upregulation of peroxisomal β-oxidation stimulates ethanol metabolism and induces liver triglyceride deposition in animals. Excessive oxidation of fatty acids by peroxisomes generates considerable hydrogen peroxide in mouse liver, which significantly enhances liver ethanol oxidation and induces hepatic triglyceride accumulation through elevating mitochondrial NADH/NAD⁺ ratio and suppressing mitochondrial fatty acid oxidation. Specific inhibition of peroxisomal β-oxidation suppresses ethanol oxidation in the liver and attenuates ethanol-induced hepatic steatosis in fasting mice. It is proposed that induction of peroxisomal β-oxidation serves as a critical mechanism for alcohol-induced hepatic lipid accumulation in animals under ketogenic state, and targeting peroxisomal β-oxidation might be a potential pathway in treating alcoholic fatty liver through reducing the supply of hydrogen peroxide and suppressing peroxisomal ethanol oxidation.