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 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 major 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.
Shimomura
I
I
Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA.
Shimano
H
H
Korn
B S
BS
Bashmakov
Y
Y
Horton
J D
JD
D001275:ATP Citrate (pro-S)-Lyase / Q000096:biosynthesis; D000818:Animals; D001835:Body Weight; D022762:CCAAT-Enhancer-Binding Proteins; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000032:analysis; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D005954:Glucosephosphate Dehydrogenase / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009249:NADP / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019301:Oleic Acid / Q000032:analysis; D009929:Organ Size; D019308:Palmitic Acid / Q000032:analysis; D010734:Phosphogluconate Dehydrogenase / Q000096:biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000032:analysis; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D009687:Nuclear Proteins; D020033:Protein Isoforms; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D014280:Triglycerides; C008757:palmitoleic acid; D019301:Oleic Acid; D019308:Palmitic Acid; D009249:NADP; D002784:Cholesterol; D008291:Malate Dehydrogenase; D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D013230:Stearoyl-CoA Desaturase; D001275:ATP Citrate (pro-S)-Lyase