Low-dose l-carnitine supplementation attenuates hepatic lipid accumulation in chow-fed mice: Insights from integrated multi-omics analysis.

Most studies on l-carnitine and hepatic lipid metabolism have focused on deficiency or HFD-associated metabolic disorders, whereas its low-dose nutritional effects under standard chow-fed conditions remain unclear. In this study, standard chow-fed C57BL/6 J mice were orally administered low doses of l-carnitine for 35 days, and hepatic responses were evaluated using phenotypic, histological, metabolomic, transcriptomic, and proteomic analyses. l-carnitine supplementation reduced liver weight and hepatic lipid accumulation in a dose-associated manner, accompanied by decreased hepatocyte area and reduced H&E-based hepatocellular vacuolation. Multi-omics integration suggests attenuation of canonical fatty acid oxidation marker activation. Instead, l-carnitine treatment was associated with attenuation of lipogenesis-related signatures, including reduced xylulose-5-phosphate abundance, decreased PPP2CB protein abundance, and lower Acaca and Fasn levels, providing evidence for a potential suppression of a Xu-5P/PP2A/ChREBP-associated lipogenic signature. Concurrent remodeling of amino acid-, carbohydrate-, pyrimidine-, and ascorbate/aldarate-related pathways further indicated coordinated regulation of substrate metabolism, nucleotide metabolism, and detoxification-associated processes. Together, these findings highlight a previously underexplored nutritional dimension of l-carnitine action, showing that low-dose supplementation can reshape hepatic lipid-associated metabolic networks even under standard chow-fed, non-HFD conditions. This study extends the current understanding of l-carnitine from a classical fatty acid transport cofactor to a dietary factor involved in the network-level regulation of hepatic lipid homeostasis.