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.