Mechanism of the slow induction of apolipoprotein A-I synthesis by retinoids in cynomolgus hepatocytes: Involvement of retinoic acid and retinoid X receptors
article
We showed previously that retinoids stimulate apolipoprotein A-I (apoA- I) synthesis in cultured cynomolgus hepatocytes only after a 24-h lag phase. Here we report on the biochemical background of the slow response, the requirement for high retinoic acid concentrations, and the involvement of different retinoid receptors. The time course of the effect of 10 μM all- trans retinoic acid (at-PA) on apoA-I mRNA levels and protein secretion were comparable, i.e., minor increases were observed after a 24-h incubation and mRNA levels were increased 2.2- and 3.5-fold after 48 h and 72 h, respectively. In contrast, apoA-I gene transcription was already increased (2.6-fold) after a 4-h incubation with 10 μM at-RA. At-RA disappeared rapidly from the cultures: after 2 h of incubation 40% of the added amount was left and after 24 h only 2%. RARβ mRNA and gene expression were increased after incubation with 10 nm at-RA, whereas RARer and RXRα mRNA levels and expression remained unchanged. No transcriptional activity and mRNA for other retinoid receptors were detectable. Both PAR-selective (TTNPB) and RXR-selective (3-methyl-TTNPB) agonists induced apoA-I synthesis at 1 and 10 μM. These results show that i) the slow increase in apoA-I secretion is caused by a slow increase of its mRNA level; ii) the apoA-I gene transcription in cynomolgus hepatocytes is induced rapidly by retinoids; iii) the added at-RA disappeared rapidly from the cultures, explaining the necessity for high initial concentrations; iv) RARα and/or RARβ and RXRα are involved in the activation of apoA-I expression by retinoids. Chemicals/CAS: 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid, 71441-28-6; alitretinoin, 5300-03-8; Apolipoprotein A-I; Benzoates; bexarotene; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; RNA, Messenger; Tetrahydronaphthalenes; Transcription Factors; Tretinoin, 302-79-4
Topics
Apolipoprotein A-ICynomolgus hepatocytesMRNARAPReceptor-selective ligandsRetinoidsRXRTranscriptional regulationApolipoprotein a1Retinoic acidRetinoid x receptorAnimal cellLipogenesisLipoprotein metabolismLiver cellLiver metabolismMonkeyNonhumanTranscription regulationAnimalsApolipoprotein A-IBenzoatesBlotting, NorthernCells, CulturedFemaleGene Expression RegulationLiverMacaca fascicularisMaleReceptors, Retinoic AcidRetinoid X ReceptorsRetinoidsRNA, MessengerTetrahydronaphthalenesTime FactorsTrans-Activation (Genetics)Transcription FactorsTretinoin
TNO Identifier
234104
ISSN
00222275
Source
Journal of Lipid Research, 38(11), pp. 2273-2280.
Pages
2273-2280