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

Previous studies have shown that the rate of fatty acid synthesis is elevat ed 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 s ynthase, whose transcription is stimulated by SREBPs. Fatty acid synthesis also requires a source of acetyl-CoA and NADPH. In the current studies we s how 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 fo und marked elevations in the mRNAs for malic enzyme, glucose-6-phosphate de hydrogenase, and 6-phosphogluconate dehydrogenase, all of which produce NAD PH. Finally, we found that overexpressing two of the SREBPs (la 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 detect ed in nontransgenic livers. This stimulation led to an increase in total SC D activity in liver microsomes, Together, all of these changes would be exp ected to lead to a marked increase in the concentration of monounsaturated fatty acids in the transgenic livers, and this was confirmed chromatographi cally. We conclude that expression of nuclear SREBPs is capable of activati ng the entire coordinated program of unsaturated fatty acid biosynthesis in mouse liver.