Dietary beta-cryptoxanthin inhibits high-refined carbohydrate diet-induced fatty liver via differential protective mechanisms depending on carotenoid cleavage enzymes in male mice

Authors: LIM, JI YE - Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AUSMAN, LYNN - Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/25/2019
Publication Date: 6/18/2019
Citation: Lim, J., Liu, C., Hu, K., Smith, D.E., Wu, D., Lamon-Fava, S., Ausman, L., Wang, X. 2019. Dietary beta-cryptoxanthin inhibits high-refined carbohydrate diet-induced fatty liver via differential protective mechanisms depending on carotenoid cleavage enzymes in male mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxz106.
DOI: https://doi.org/10.1093/jn/nxz106

Interpretive Summary: Beta-Cryptoxanthin (BCX), a provitamin A carotenoid found primarily in red sweet peppers, has been shown to be protective against nonalcoholic fatty liver disease (NAFLD). In the present study, we investigated whether BCX feeding inhibits high refined-carbohydrate diet-induced NAFLD, dependent on, or independent of carotenoid cleavage enzymes, BCO1/BCO2. In the present study, we provided evidence that dietary BCX is effective in the prevention of the development of high refined-carbohydrate diet-induced NAFLD in both BCO1/BCO2 double knock-out mice and corresponding wild type mice. However, our data suggest that the mechanisms involved are different in wild type and double knock-out mice, indicating the BCX molecule, when not cleaved, has independent functions. The BCX-induced mitigation of hepatic steatosis despite the absence of BCO1/BCO2 implies that dietary intact BCX plays a role in the prevention of NAFLD. Importantly, we revealed that the protective effects of BCX against NAFLD are achieved through different molecular mechanisms depending on carotenoid cleavage enzymes.

Technical Abstract: Background: Beta-Cryptoxanthin (BCX), a provitamin A carotenoid, has been shown to be protective against nonalcoholic fatty liver disease (NAFLD). BCX can be cleaved by beta-carotene-15, 15'-oxygenase (BCO1) to generate vitamin A, and by beta-carotene-9', 10'-oxygenase (BCO2) to produce bioactive apo-carotenoids. BCO1/BCO2 polymorphisms have been associated with variations in the status of human and animal carotenoid levels. Objectives: We investigated whether BCX feeding inhibition of high refined-carbohydrate diet (HRCD)-induced NAFLD is dependent or independent of BCO1/BCO2. Methods: BCO1-/-/BCO2-/- double KO (DKO) mice and wild type (WT) mice were randomly fed to either an HRCD or HRCD with BCX (10 mg/kg diet, equivalent to the daily human consumption of 3-4 ounces of a sweet red peppers) for 24 weeks. Results: BCX feeding significantly reduced hepatic steatosis severity and total cholesterol levels, in both WT and DKO mice compared to their respective HRCD counterparts (P < 0.01 and P < 0.001, respectively). Hepatic levels of BCX, but not retinol and retinyl palmitate, were significantly higher (33-fold) in the DKO mice than in the WT mice. In WT mice, BCX-mitigated steatosis was significantly (P < 0.05) associated with increased hepatic lipid beta-oxidation (PPARalpha, ACOX1) and cholesterol efflux (ABCG5), and with suppressed lipogenesis (ACC) in the mesenteric adipose tissue (MAT). In DKO mice, the protection of BCX was significantly (P < 0.05) associated with decreased lipogenesis (FAS, ACC1, and ACC2), cholesterol synthesis (HMGCoA-R) and increased cholesterol catabolism (CYP7A1). BCX feeding increased hepatic mRNA expressions of farnesoid X receptor and decreased expressions of inflammatory cytokines (IL-6 and IL-4) in the MAT, which were associated with significantly increased sirtuin 1 levels in the liver and MAT (P < 0.05). Conclusion: The present study provides compelling evidence that BCX prevents HRCD-induced NAFLD through different mechanisms, depending on the presence or absence of BCO1/BCO2.