Phytoene, a Precursor of Lycopene in Tomatoes, Protects Against Metabolic Dysfunction‐Associated Steatotic Liver Disease in Mice

The health benefits of tomato consumption may derive from bioactive compounds other than lycopene in tomatoes. 15‐ Cis ‐phytoene, a colorless precursor of lycopene abundant in tomatoes, has not been well studied for its biological activity. We investigated whether dietary 15‐ cis ‐phytoene protects against metabolic dysfunction‐associated steatotic liver disease (MASLD) and whether this protection depends on the carotenoid cleavage enzymes, beta‐carotene‐15,15’‐oxygenase 1 (BCO1) and beta‐carotene‐9’,10’‐oxygenase (BCO2). Wild‐type (WT) and BCO1 −/− /BCO2 −/− double knock‐out (DKO) mice were fed a high‐refined carbohydrate diet (HRCD) with or without 15‐ cis ‐phytoene supplementation for 24 weeks. 15‐ Cis ‐phytoene supplementation markedly increased 15‐ cis and all‐ trans phytoene concentrations in intestine, liver, and serum, and significantly attenuated HRCD‐induced MASLD in WT mice. The protective effects of phytoene on MASLD in WT mice were associated with increased hepatic mRNA and protein levels of SIRT1, PGC1α, and PPARα; enhanced AMPK and ACC phosphorylation; and upregulated fatty acid oxidation genes, but not with the gut microbiota composition. Despite much higher phytoene accumulation in the liver and serum, phytoene did not exhibit protection against HRCD‐induced MASLD in DKO mice. Phytoene is a biologically active compound that contributes to the benefits of tomato consumption against MASLD. Its protective effects are likely mediated by cleavage metabolites through BCO1/BCO2.