Poster Topical Area: Carotenoids and Retinoids
Poster Board Number: 13
(Background) Non-alcoholic fatty liver disease (NAFLD) is the most commonly occurring chronic liver disease worldwide. Both genetic and environmental factors are related to susceptibility to NAFLD. β-carotene-15, 15'-oxygenase (BCO1) and β-carotene-9', 10'-oxygenase (BCO2) are essential enzymes in carotenoid metabolism. While BCO1/BCO2 polymorphisms have been associated with alterations to human and animal carotenoid levels, recent studies have suggested that BCO1 or BCO2 may have specific functions beyond the cleavage of carotenoids. (Objectives) In the present study, we investigated the effect of ablation of both BCO1/BCO2 in the development of NAFLD and its underlying molecular mechanism(s). (Methods) Wild type mice (WT, n=8) and BCO1/BCO2 double knockout mice (BCO1/BCO2 DKO, n=8) of a C57BL/6J genetic background, were fed standard rodent chow diet for 24 weeks. (Results) There were no changes in body weight or liver weights between WT and BCO1/BCO2 DKO groups. However, all BCO1/BCO2 DKO mice developed liver steatosis (8/8) and had significantly higher levels of hepatic triglyceride and total cholesterol levels in the liver and plasma compared to WT (0/8, P < 0.05). These hepatic changes in the BCO1/BCO2 DKO mice were associated with significant: 1) increases in mRNA and protein levels of lipogenesis markers (SCD1, ACC, CD36), and decreases in the gene expressions of fatty acid β-oxidation markers (CPT-1, SIRT3, PPARα); 2) upregulation of the cholesterol metabolism markers (CYP7A1, CYP8B1, HMG-CoAR); 3) alterations to the microRNAs (miR-34a, miR-33, miR-122) related to TG accumulation and cholesterol metabolism; 4) increases in hepatic oxidative stress markers (HO-1, SOD1, SOD2, GPX, catalase); and 5) decreases in nuclear protein levels of farnesoid X receptor (FXR), and mRNA levels of FXR, small heterodimer partner (SHP), and sirtuin 1 (SIRT1). (Conclusion) Taken together, the present study provided novel experimental evidence that the ablation of both BCO1/BCO2 led to the development of NAFLD, indicating that BCO1/BCO2 could play a significant role in maintaining normal hepatic lipid and cholesterol homeostasis, potentially through the activation of the FXR/miR-34a/SIRT1 pathway.
Supported by NIFA/AFRI (2017-67017-26363) and USDA/ARS (58-1950-0074)
Ji Ye Lim
graduate student (Ph.D)
1) Nutrition and Cancer Biology Lab, JM USDA-HNRCA at Tufts University, Boston, MA, USA, and 2) Biochemical and Molecular Nutrition Program, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA