Hepatic stellate cells are an important cellular site for β-carotene conversion to retinoid

Department of Medicine, Columbia University, New York, NY 10032, USA.
Archives of Biochemistry and Biophysics (Impact Factor: 3.02). 12/2010; 504(1):3-10. DOI: 10.1016/
Source: PubMed


Hepatic stellate cells (HSCs) are responsible for storing 90-95% of the retinoid present in the liver. These cells have been reported in the literature also to accumulate dietary β-carotene, but the ability of HSCs to metabolize β-carotene in situ has not been explored. To gain understanding of this, we investigated whether β-carotene-15,15'-monooxygenase (Bcmo1) and β-carotene-9',10'-monooxygenase (Bcmo2) are expressed in HSCs. Using primary HSCs and hepatocytes purified from wild type and Bcmo1-deficient mice, we establish that Bcmo1 is highly expressed in HSCs; whereas Bcmo2 is expressed primarily in hepatocytes. We also confirmed that HSCs are an important cellular site within the liver for accumulation of dietary β-carotene. Bcmo2 expression was found to be significantly elevated for livers and hepatocytes isolated from Bcmo1-deficient compared to wild type mice. This elevation in Bcmo2 expression was accompanied by a statistically significant increase in hepatic apo-12'-carotenal levels of Bcmo1-deficient mice. Although apo-10'-carotenal, like apo-12'-carotenal, was readily detectable in livers and serum from both wild type and Bcmo1-deficient mice, we were unable to detect either apo-8'- or apo-14'-carotenals in livers or serum from the two strains. We further observed that hepatic triglyceride levels were significantly elevated in livers of Bcmo1-deficient mice fed a β-carotene-containing diet compared to mice receiving no β-carotene. Collectively, our data establish that HSCs are an important cellular site for β-carotene accumulation and metabolism within the liver.

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Available from: Kenneth M Riedl, Jun 10, 2014
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    • "BC treatment of HepaRG hepatocytes produced a significant reduction in intracellular RBP4 levels in a range of concentrations between 1.8 and 15 lM, indicating that BCMO1 is active in these cells. This key enzyme in retinoid metabolism was shown to be expressed, although at levels significantly lower than in vivo, in some cell lines such as intestinal Caco-2/TC7 cells (During et al., 1998b), 3T3 adipocytes (Lobo et al., 2010), and stellate cells (Shmarakov et al., 2010), but its activity has to date never been described in hepatic cell lines, including HepG2 cells (During et al., 1998b). BCMO1 expression will be further investigated in 3A and HepaRG cell to better characterize their response to carotenoids. "
    C. Rossi · B. Guantario · S. Ferruzza · C. Guguen-Guillouzo · Y. Sambuy · M. L. Scarino · D. Bellovino
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    ABSTRACT: Dietary retinoid bioavailability involves the interplay of the intestine (transport and metabolism) and the liver (secondary metabolism). To reproduce these processes in vitro, differentiated human intestinal Caco-2/TC7 cells were co-cultured with two hepatocyte cell lines. Murine 3A cells and the more highly differentiated human HepaRG hepatocytes were both shown to respond to beta-carotene (BC) and retinol (ROH) treatment by secreting Retinol Binding Protein 4 (RBP4). In co-culture experiments, Caco-2/TC7 were differentiated on filter inserts and transferred for the time of the experiment to culture wells containing confluent 3A or differentiated HepaRG cells. Functionality of the co-cultures was assayed using as endpoints the retinol-dependent secretion of RBP4 and the retinoic acid-dependent induction of CYP26A1 in hepatocytes. BC and ROH added to intestinal Caco-2/TC7 induced a reduction in intracellular RBP4 levels in the underlying hepatocytes and its secretion into the medium. HepaRG hepatocytes were also shown to up-regulate the expression of CYP26A1 mRNA in response to retinoid treatment. This in vitro model represents a useful tool to analyze the absorption and metabolism of retinoids and could be further developed to investigate other dietary compounds and molecules of pharmacological interest.
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