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Deficiency of β, β‐Carotene‐9′, 10′‐Oxygenase 2 Links to Systemic Inflammation, Dyslipidemia and Glucose Intolerance
Author(s) -
Wu Lei,
Guo Xin,
Lyu Yi,
Clarke Stephen L.,
Lucas Edralin A.,
Smith Brenda J.,
Wang Weiqun,
Medeiros Denis M.,
Shen Xinchun,
Lin Dingbo
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.797.16
Subject(s) - endocrinology , medicine , lipogenesis , gluconeogenesis , lipid metabolism , biology , adipose tissue , carbohydrate metabolism , inflammation , dyslipidemia , hepatocyte , white adipose tissue , fatty liver , chemistry , biochemistry , metabolism , diabetes mellitus , disease , in vitro
Objective The β,β‐carotene‐9′,10′‐oxygenase2 (BCO2) is a mitochondrial inner membrane protein broadly presented in mammals. It was initially discovered as an enzyme that catalyzes the asymmetric cleavage of carotenoids. Recently we have found that BCO2 knockout (KO) mice are more prone to obesity and diabetes. Therefore, the aim of this study was to investigate the mechanism by which BCO2 regulates lipid and glucose metabolism in human primary hepatocytes in culture and in BCO2 KO mice. Methods Human primary hepatocytes, HepG2 cells, and BCO2 knockout mice were used as experimental models. Quantitative real time PCR and Western blot were used for gene expression analysis. Untargeted metabolomics, the tolerance tests of glucose, insulin and pyruvate, and blood metabolic profiling were also performed. Results The results showed the declined expression of BCO2 protein in primary hepatocyte cultures exposed to high palmitate and/or glucose challenges. BCO2 protein expression was significantly suppressed in HepG2 cells, compared to the human primary hepatocytes. Over‐expression of human BCO2 attenuated lipid accumulation and intracellular oxidative stress in HepG2 cells. Deficiency of BCO2 caused higher mitochondrial respiratory activities, mitochondrial stress, systemic inflammation, elevation of non‐esterified fatty acids and fasting blood glucose, and glucose intolerance in young adult mice. Moreover, depletion of BCO2 resulted in enhanced de novo lipogenesis and gluconeogenesis, and accumulation of diacylglycerol in the liver tissues. However, the whole body fat content and the uptake of circulating lipids and glucose by muscles and/or white adipose tissues were not changed or even decreased in KO mice. Conclusions Collectively, the functional and metabolic data suggested that BCO2 contributes to normal mitochondrial function. Loss of BCO2 leads to mitochondrial dysfunction, oxidative stress, and subsequent metabolic disorders in mice.