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BACKGROUND: β-cryptoxanthin (BCX), one of the major carotenoids detected in human circulation, can protect against the development of fatty liver disease. BCX can be metabolized through β-carotene-15,15'-oxygenase (BCO1) and β-carotene-9',10'-oxygenase (BCO2) cleavage pathways to produce both vitamin A and apo-carotenoids, respectively, which are considered important signaling molecules in a variety of biological processes. Recently, we have demonstrated that BCX treatment reduced hepatic steatosis severity and hepatic total cholesterol levels in both wide type and BCO1(–/–)/BCO2(–/–) double knock out (KO) mice. Whether the protective effect of BCX is seen in single BCO2(–/–) KO mice is unclear. METHODS: In the present study, male BCO2(–/–) KO mice at 1 and 5 months of age were assigned to two groups by age and weight-matching as follows: (I) –BCX control diet alone (AIN-93 purified diets); (II) +BCX 10 mg (supplemented with 10 mg of BCX/kg of diet) for 3 months. At 4 and 8 months of age, hepatic steatosis and inflammatory foci were evaluated by histopathology. Retinoids and BCX concentrations in liver tissue were analyzed by high-performance liquid chromatography (HPLC). Hepatic protein expressions of SIRT1, acetylated and total FoxO1, PGC1α, and PPARα were determined by the Western blot analysis. Real-time PCR for gene expressions (MCAD, SCD1, FAS, TNFα, and IL-1β gene expression relative to β-actin) was conducted in the liver. RESULTS: Steatosis was detected at 8 months but not at 4 months of age. Moreover, BCX supplementation significantly reduced the severity of steatosis in the livers of BCO2 KO mice, which was associated with changes in hepatic SIRT1 acetylation of FOXO1, PGC1α protein expression and PPARα protein expression in BCO2(–/–) KO mice. HPLC analysis showed that hepatic BCX was detected in BCX supplemented groups, but there were no differences in the hepatic levels of retinol and retinyl palmitate (RP) among all groups. CONCLUSIONS: The present study provided experimental evidence that BCX intervention can reduce liver steatosis independent of BCO2.