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

Arch Biochem Biophys. 2018 Sep 15;654:1-9. doi: 10.1016/j.abb.2018.07.007. Epub 2018 Jul 11.

Abstract

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, 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 β-oxidation markers; 2) upregulation of cholesterol metabolism markers; 3) alterations to microRNAs related to TG accumulation and cholesterol metabolism; 4) increases in an hepatic oxidative stress marker (HO-1) but decreases in 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 and 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.

Keywords: Carotenoid cleavage enzymes; Farnesoid X receptor; Fatty liver disease; Sirtuin 1.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Carotenoids / metabolism*
  • Cholesterol / metabolism
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Hydrolysis
  • Lipid Metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Oxidative Stress
  • Polymorphism, Single Nucleotide
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sirtuin 1 / metabolism*
  • Triglycerides / metabolism
  • beta-Carotene 15,15'-Monooxygenase / genetics
  • beta-Carotene 15,15'-Monooxygenase / metabolism*

Substances

  • Biomarkers
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Receptors, Cytoplasmic and Nuclear
  • Triglycerides
  • farnesoid X-activated receptor
  • Carotenoids
  • Cholesterol
  • Dioxygenases
  • Bco1 protein, mouse
  • Bco2 protein, mouse
  • beta-Carotene 15,15'-Monooxygenase
  • Sirt1 protein, mouse
  • Sirtuin 1