Xanthophyll beta-cryptoxanthin treatment inhibits hepatic steatosis without altering vitamin A status in beta-carotene 9'10'-oxygenase knockout mice

Authors: LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RAFACHO, BRUNO PAOLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Hepatobiliary Surgery and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2020
Publication Date: 8/1/2020
Citation: Liu, C., Rafacho, B.M., Wang, X. 2020. Xanthophyll beta-cryptoxanthin treatment inhibits hepatic steatosis without altering vitamin A status in beta-carotene 9'10'-oxygenase knockout mice. Hepatobiliary Surgery and Nutrition. https://doi.org/10.21037/hbsn-20-404.
DOI: https://doi.org/10.21037/hbsn-20-404

Interpretive Summary: High intake of beta-cryptoxanthin, one of the major carotenoids found at high levels in sweet red peppers and citrus fruits, protects against the development of nonalcoholic fatty liver disease (NAFLD). In this animal model study we found that beta-cryptoxanthin feeding significantly reduced the severity of NAFLD and increased the response of several key molecular markers (PGC1alpha and PPARalpha protein expression) related to lipid metabolism. Beta-cryptoxanthin level increased in livers of mice fed with beta-cryptoxanthin, but there were no differences in the liver vitamin A (retinol and retinyl palmitate) levels among all groups. The study provided experimental evidence that beta-cryptoxanthin feeding, independent of vitamin A, can reduce NAFLD development in mice.

Technical Abstract: Background: Xanthophyll beta-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 beta-carotene-15,15'-oxygenase (BCO1) and beta-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 dependent on single BCO2-/- KO mice is unclear. Methods: In the present study, male BCO2-/- KO mice at 1 month and 5 months of age were assigned to two groups by age and weight-matching as follows: (I) -BCX control diet alone; (II) +BCX 10 mg (supplemented with 10 mg of BCX/kg of diet) for 3 months. At 4 months and 8 months of age, hepatic steatosis and inflammatory foci were evaluated by histopathology. Retinoids and BCX concentrations in liver tissue were analyzed by HPLC. Hepatic protein expressions of BCO1, SIRT1, acetylated and total FoxO1, PGC1alpha, and PPARalpha were determined by the Western blot analysis. Real-Time PCR for gene expressions (MCAD, SCD1, FAS, TNFalpha, and IL-1beta gene expression relative to beta-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, PGC1alpha protein expression and PPARalpha 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 among all groups. Conclusions: The present study provided experimental evidence that BCX intervention can reduce liver steatosis independently of BCO2.