β-carotene regulates expression of β-carotene 15,15'-monoxygenase in human alveolar epithelial cells.
β-Carotene 15,15'-monooxygenase (CMO1, BCMO1) converts β-carotene to retinaldehyde (retinal) and is a key enzyme in vitamin A metabolism. CMO1 activity is robust in the intestine and liver, where cmo1 gene transcription may be subject to negative feedback by accumulation of its metabolic products. Evidence from CMO1 null animals also indicates that non-gastrointestinal CMO1 may be required for tissue-specific conversion of β-carotene into vitamin A. The aim of this study was to investigate the effects of the enzymatic substrate, β-carotene, on regulation of CMO1 in a cell model of human alveolar pneumocytes. We demonstrate that CMO1 is expressed in human alveolar epithelial (A549) cells and converts β-carotene into retinal and biologically active retinoic acids (RA). Exposure to β-carotene suppresses CMO1 expression at both mRNA and protein levels. β-Carotene, but not all-trans RA, decreases CMO1 promoter activity in a time- and dosage-dependent manner. This β-carotene-mediated inhibition of CMO1 expression results from decreased binding of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα) in the CMO1 promoter. β-Carotene treatment also antagonizes PPARγ activity in HEK293 cells that stably express CMO1 wild-type, but not in cells that express the CMO1 mutant or vector alone. These findings have implications for local vitamin A synthesis in the lung, especially during systemic vitamin A insufficiency and may also help to explain, in part, the mechanism underlying the increased lung cancer risk upon β-carotene supplementation in smokers.
Department of Pediatrics, Texas Tech University Health Science Center, Paul L. Foster School of Medicine, El Paso, TX 79905, USA.
Xiaoming
X
Gong
Raju
R
Marisiddaiah
Lewis P
LP
Rubin
D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D019207:beta Carotene / Q000378:metabolism / Q000502:physiology*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
D047495:PPAR gamma; D019207:beta Carotene; D050559:beta-Carotene 15,15'-Monooxygenase
Alveolar epithelium; PPARγ; RXRα; Retinaldehyde; Retinoic acid; Transcriptional regulation; β-Carotene 15,15′-monooxygenase