Abstract
In addition to being essential for the transcription of genes involved in cellular lipogenesis, increasing evidence associates sterol regulatory element binding proteins (SREBPs) with the transcriptional control of carbohydrate metabolism. The aim of this study was to assess the effect of overexpression SREBP1a, a potent activator of all SREBP-responsive genes, on the intermediary metabolism of Sparus aurata, a glucose-intolerant carnivorous fish. Administration of chitosan-tripolyphosphate nanoparticles complexed with a plasmid driving expression of the N-terminal transactivation domain of SREBP1a significantly increased SREBP1a mRNA and protein in the liver of S. aurata. Overexpression of SREBP1a enhanced the hepatic expression of key genes in glycolysis-gluconeogenesis (glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase), fatty acid synthesis (acetyl-CoA carboxylase 1 and acetyl-CoA carboxylase 2), elongation (elongation of very long chain fatty acids protein 5) and desaturation (fatty acid desaturase 2) as well as reduced nicotinamide adenine dinucleotide phosphate production (glucose-6-phosphate 1-dehydrogenase) and cholesterol synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase), leading to increased blood triglycerides and cholesterol levels. Beyond reporting the first study addressing in vivo effects of exogenous SREBP1a in a glucose-intolerant model, our findings support that SREBP1a overexpression caused multigenic effects that favoured hepatic glycolysis and lipogenesis and thus enabled protein sparing by improving dietary carbohydrate conversion into fatty acids and cholesterol.
Highlights
The sterol regulatory element binding protein (SREBP) family of transcription factors has a major role in regulating the expression of genes that control cellular lipid biosynthesis [1,2].SREBPs are synthesized as membrane-bound precursors that remain anchored to the endoplasmicBiomolecules 2019, 9, 297; doi:10.3390/biom9080297 www.mdpi.com/journal/biomoleculesBiomolecules 2019, 9, 297 reticulum membrane
S. aurata, ionic gelation was used to obtain chitosan-TPP nanoparticles complexed with an expression vector encoding the N-terminal nuclear fragment of hamster SREBP1a, which was shown to transactivate S. aurata GK and PFKFB1 genes in previous studies [20,21]
SREBP1a was found for the expression levels of acetyl-CoA carboxylase 1 (ACC1), biosynthesis of fatty acids and cholesterol [1], we studied the effect of chitosan-TPP-pSG5-SREBP1a which increasedon
Summary
The sterol regulatory element binding protein (SREBP) family of transcription factors has a major role in regulating the expression of genes that control cellular lipid biosynthesis [1,2].SREBPs are synthesized as membrane-bound precursors that remain anchored to the endoplasmicBiomolecules 2019, 9, 297; doi:10.3390/biom9080297 www.mdpi.com/journal/biomoleculesBiomolecules 2019, 9, 297 reticulum membrane. The sterol regulatory element binding protein (SREBP) family of transcription factors has a major role in regulating the expression of genes that control cellular lipid biosynthesis [1,2]. The C-terminal domain of SREBP precursors associates with a sterol sensor, the SREBP-cleavage activating protein (Scap), which in turn interacts with insulin-induced gene (Insig) protein [3,4]. The activity of alternate promoters in the srebf gene generates two isoforms of SREBP1 in mammals (SREBP1a and SREBP1c), while a second gene, srebf, encodes for the SREBP2 protein [7]. SREBP1c primarily transactivates genes required for fatty acid and triglyceride synthesis, while SREBP2 regulates the transcription of genes associated with cholesterol metabolism [7,11].
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