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Title: Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway

Author
item LIM, JI YE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Archives of Biochemistry and Biophysics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/9/2018
Publication Date: 7/11/2018
Citation: Lim, J., Liu, C., Hu, K., Smith, D.E., Wang, X. 2018. Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway. Archives of Biochemistry and Biophysics. 654:1-9. https://doi.org/10.1016/j.abb.2018.07.007.
DOI: https://doi.org/10.1016/j.abb.2018.07.007

Interpretive Summary: B-Carotene cleavage enzymes (B-Carotene-15, 15'-oxygenase (BCO1) and B-carotene-9', 10'-oxygenase (BCO2)) are essential enzymes in the metabolism of B-Carotene. While genetic alterations of BCO1/BCO2 have been associated with changes to human and animal carotenoid levels, experimental studies have suggested that BCO1 and BCO2 may have other functions. We found that animals that lack the BCO1/BCO2 snzymes developed fatty liver and had significantly higher levels of hepatic and plasma triglycerides and total cholesterol. These effects were associated with increased markers for oxidative stress in the liver, fat synthesis and cholesterol metabolism, but decreased anti-oxidant enzymes, and sirtuin 1. Taken together, the present study provided novel experimental evidence that the absence of both BCO1/BCO2 enzymes led to the development of fatty liver disease, indicating that these enzymes could play a role in maintaining normal liver fat and cholesterol metabolism.

Technical Abstract: B-Carotene-15, 15'-oxygenase (BCO1) and B-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, experimental studies have suggested that BCO1 and BCO2 may have specific physiological functions beyond the cleavage of carotenoids. In the present study, we investigated the effect of ablation of both BCO1/BCO2 in the development of non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism(s). BCO1/BCO2 double knock out (DKO) mice developed hepatic steatosis (8/8) and had significantly higher levels of hepatic and plasma triglyceride and total cholesterol compared to WT (0/8). Hepatic changes in the BCO1/BCO2 DKO mice were associated with significant: 1) increases in lipogenesis markers, and decreases in fatty acid B-oxidation markers; 2) upregulation of the cholesterol metabolism markers; 3) alterations to the microRNAs related to TG accumulation and cholesterol metabolism; 4) increases in hepatic oxidative stress marker (HO-1) but decreases, anti-oxidant enzymes; and 5) decreases in farnesoid X receptor (FXR), small heterodimer partner (SHP), and sirtuin 1 (SIRT1). The present study provided novel experimental evidence that BCO1/BCO2 could play a significant role in maintaining normal hepatic lipid and cholesterol homeostasis, potentially through the regulation of the FXR/miR-34a/SIRT1 pathway.