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The majority of research has suggested that α-lipoic acid (ALA) is a potential therapeutic agent for chronic diseases associated with oxidative stress, including atherosclerosis, diabetes, and neurodegeneration. Therefore, a nutritional supplementation with ALA is recommended although the effects of a short- and long-term intake of ALA on central organs in healthy individuals are not studied in detail yet. Therefore, liver tissue of 4 and 74 weeks ALA-treated healthy C57BL6/J mice with respect to lipid metabolism was analyzed. In doing so, it was shown that short-term and long-term ALA treatment caused a marked increase of β-oxidation, as indicated by a significant rise of mRNA expression of fgf21, pparα, and its target genes, for example, acox1, cpt1α, and cpt2, as well as of Fgf21 plasma concentration. Glycolytic activity, as assessed by pklr1 mRNA expression and pyruvate kinase activity, was also found increased. In addition, it was shown that both short- and long-term ALA treatment increased cholesterol content, induced systemic triglyceridemia, and enhanced rxrα and lxrα mRNA expression. Despite the fact that short-term ALA intake reduced lipogenesis, as given by significant declines of fas and srebp1c mRNA expression, and that a long-term ALA intake induced a significant rise of these lipogenic genes, both treatment regimen caused fat accumulation. This, however, was more pronounced upon long-term ALA intake, leading to hepatic steatosis and liver injury, as indicated by increased inflammation and disruption of the general hepatic architecture. In summary, the prophylactic and abundant use of ALA under healthy conditions should be considered with caution.