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Differential expression of cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl CoA synthases during adipocyte differentiation

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Abstract

Mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl CoA synthase (m-HMS and c-HMS) genes show high identity at the nucleotide and amino acid level, but no homology has been found in the promoter area. The main regulator for c-HMS is SREBP. The best known transcription factor that regulates m-HMS is PPARα. Three types of PPAR, α, γ and δ have been described in vertebrates. Here we found that they display distinct ligand response profiles in the m-HMS promoter. In some conditions PPARγ is a significant activator of m-HMS. Thus, the m-HMS gene is transiently expressed during the clonal expansion phase of 3T3-L1 differentiation. We found that C/EBPδ and PPARγ activate the m-HMS promoter in 3T3-L1 cells synergistically. This synergistic effect was only observed in the whole promoter (–1148 to +28). A small construct (–116 to +28) which contains the PPRE did not respond to C/EBPδ and/or PPARγ. This suggests that a putative C/EBP site lie somewhere between –1148 and –116 bp. We also show that C/EBPδ was more efficient that C/EBPα and C/EBPβ to activate the m-HMS promoter. The time course of c-HMS mRNA expression during 3T3-L1 differentiation was different, with a significant increase at terminal adipogenesis. We found that the transcription factor C/EBPα did not activate the c-HMS promoter. The differential pattern of expression shown by these two genes, which have a common ancestor, exemplifies refinements of transcriptional control during evolution.

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  1. Departament de Bioquímica i Biologia Molecular, Facultat de Farmaàcia, Unitat de Bioquímica, Avd. Diagonal 643, E 08028, Barcelona, Spain

    J.M. Lopez, F.G. Hegardt & D. Haro

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  3. D. Haro
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Lopez, J., Hegardt, F. & Haro, D. Differential expression of cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl CoA synthases during adipocyte differentiation. Mol Cell Biochem 217, 57–66 (2001). https://doi.org/10.1023/A:1007284217886

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