Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver

Iichiro Shimomura, Hitoshi Shimano, Bobby S. Korn, Yuriy Bashmakov, Jay D. Horton

Research output: Contribution to journalArticle

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Abstract

Previous studies have shown that the rate of fatty acid synthesis is elevated by more than 20-fold in livers of transgenic mice that express truncated nuclear forms of sterol regulatory element-binding proteins (SREBPs). This was explained in part by an increase in the levels of mRNA for the two maj or enzymes of fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase, whose transcription is stimulated by SREBPs. Fatty acid synthesis also requires a source of acetyl-CoA and NADPH. In the current studies we show that the levels of mRNA for ATP citrate lyase, the enzyme that produces acetyl-CoA, are also elevated in the transgenic livers. In addition, we found marked elevations in the mRNAs for malic enzyme, glucose- 6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase, all of which produce NADPH. Finally, we found that overexpressing two of the SREBPs (1a and 2) led to elevated mRNAs for stearoyl-CoA desaturase 1 (SCD1), an isoform that is detectable in nontransgenic livers, and SCD2, an isoform that is not detected in nontransgenic livers. This stimulation led to an increase in total SCD activity in liver microsomes. Together, all of these changes would be expected to lead to a marked increase in the concentration of monounsaturated fatty acids in the transgenic livers, and this was confirmed chromatographically. We conclude that expression of nuclear SREBPs is capable of activating the entire coordinated program of unsaturated fatty acid biosynthesis in mouse liver.

Original languageEnglish (US)
Pages (from-to)35299-35306
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number52
DOIs
StatePublished - Dec 25 1998

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Sterol Regulatory Element Binding Proteins
Biosynthesis
Unsaturated Fatty Acids
Liver
Transgenic Mice
Genes
Messenger RNA
Acetyl Coenzyme A
Fatty Acids
NADP
Protein Isoforms
Sterol Regulatory Element Binding Protein 2
Enzymes
ATP Citrate (pro-S)-Lyase
Stearoyl-CoA Desaturase
Sterol Regulatory Element Binding Protein 1
Phosphogluconate Dehydrogenase
Acetyl-CoA Carboxylase
Fatty Acid Synthases
Monounsaturated Fatty Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. / Shimomura, Iichiro; Shimano, Hitoshi; Korn, Bobby S.; Bashmakov, Yuriy; Horton, Jay D.

In: Journal of Biological Chemistry, Vol. 273, No. 52, 25.12.1998, p. 35299-35306.

Research output: Contribution to journalArticle

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