(P04-06-26) Sexually Dimorphic Responses to the Precursor of Carotenoids 15-cis-Phytoene Feeding in Metabolic Dysfunction-Associated Steatotic Liver Disease Mouse Model

Objectives: We have previously shown that supplementation with 15-cis-phytoene, a colorless precursor of lycopene abundant in tomatoes, protects against high-refined carbohydrate diet (HRCD)-induced metabolic dysfunction–associated steatotic liver disease (MASLD) in mice. However, the effects of sexual dimorphism on the absorption and metabolism of phytoene have not been examined. We investigated whether sexually dimorphic responses to phytoene supplementation occur in male and female wild-type (WT) mice and in beta-carotene-15,15′-oxygenase 1 (BCO1) and beta-carotene-9′,10′-oxygenase (BCO2) double knockout (DKO) mice.

Methods: WT and DKO mice were fed an HRCD to induce MASLD, with or without 15-cis-phytoene supplementation (10 mg/kg diet), for 24 weeks.

Results: 15-cis-phytoene supplementation significantly attenuated HRCD-induced MASLD in both male and female WT mice, but not in DKO mice, despite significantly higher accumulation of phytoene in the intestinal mucosa, liver, and serum of DKO mice. Pronounced sex-dependent differences in phytoene accumulation and isomer distribution were observed in both WT and DKO mice. In the intestinal mucosa, females showed lower total phytoene concentrations than males; however, the 15-cis:all-trans isomer distribution was comparable between sexes. Females exhibited higher intestinal expression of the carotenoid transporter Sr-b1, whereas expression of chylomicron assembly and export genes (Apob and Mttp) did not differ between sexes. In the liver and serum, females had significantly higher total phytoene concentrations than males in both WT and DKO mice. The 15-cis isomer predominated in the liver and serum of female mice, whereas male mice showed relative enrichment of the all-trans isomer in these tissues. Hepatic expression of Apoe, Lrp, and Cd36, which are involved in hepatic uptake and clearance of chylomicron remnants, was significantly higher in females than in males.

Conclusions: The present study suggests that female mice exhibit more efficient transport of phytoene from the intestine to the liver. Moreover, the protective effects of phytoene against MASLD are likely mediated by cleavage metabolites generated through BCO1/BCO2 rather than by intact phytoene.

Funding Sources: This work was supported by USDA/ARS and NIFA/AFRI Grants.