Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway
The genes HMGCS2 and HMGCL encode the two main enzymes for ketone-body synthesis, mitochondrial HMG-CoA synthase and HMG-CoA lyase. Here, we identify and describe possible splice variants of these genes in human tissues. We detected an alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively. All splice variants maintained the reading frame. However, Western blot studies and overexpression measurements in eukaryotic or prokaryotic cell models did not reveal HL or mHS protein variants. Both genes showed a similar distribution of the inactive variants in different tissues. Surprisingly, the highest percentages were found in tissues where almost no ketone bodies are synthesized: heart, skeletal muscle and brain. Our results suggest that alternative splicing might coordinately block the two main enzymes of ketogenesis in specific human tissues.
KeywordsHMGCL HMGCS2 Ketone bodies Alternative splicing
This study was supported by grants from: Diputación General de Aragón (Ref.# Grupo Consolidado B20); University of Zaragoza UZ2007-BIO-13); Spanish Ministry of Education and Science (Ref.# SAF2004-06843-C03), Instituto de Salud Carlos III (CIBER Fisiopatología de la Obesidad y Nutrición), and European Union (FP7-223431 “Divinocell” project; to P.G.-P.). Financial support from the “Fundación Ramón Areces” to CBMSO is also acknowledged. J-J.W. was a recipient of a Torres-Quevedo fellowship financed by Ministerio de Ciencia e Innovación and M.E.T.R. from University of Zaragoza (PIF-UZ-2009-BIO-02). We also thank “Centro de Cálculo Científico” (CCCUAM) for computational support. Work at Biomol-Informatics SL was partially financed by the European Social Fund.
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