Sterol Regulatory Element Binding Protein 1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl Coenzyme A Carboxylase 2

Abstract

We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.Sterol regulatory element binding proteins (SREBPs) are transcriptional regulatory proteins that activate lipid metabolic genes in eukaryotic organisms. While there is a single SREBP gene that expresses a single protein isoform in species from fission yeast to insects, two distinct genes, SREBF1 and SREBF2, are present in humans and other mammals (9). Although forced overexpression and gene-targeting studies indicate that SREBF-1 and SREBF-2 are preferentially associated with the activation of genes for fatty acid or cholesterol biosynthesis, respectively, the differential roles for the two major SREBF1 isoforms, SREBP-1a and SREBP-1c, require further study. The two SREBP-1 proteins are identical aside from amino-terminal domains encoded by alternate first exons of the gene. SREBP-1c lacks critical residues (relative to SREBP1a) that mediate efficient interaction with CBP/p300 and the RNA polymerase II mediator complex, so the two proteins differ only in their ability to recruit coactivator proteins to stimulate transcription after DNA binding (20). Both SREBP-1 transcripts are ubiquitously expressed; however, the ratio varies over a 100-fold range in different tissues (18).An engineered deletion at the Srebf1 locus that targets both SREBP-1 isoforms simultaneously in mice, results in significant embryonic lethality and most mice die at embryonic day 10, but ϳ15% of the mutant mice survive. Interestingly, all of the survivors display increased SREBP-2 expression, suggesting that SREBP-1 is required for viability but that elevated levels of SREBP-2 can compensate for the loss of all SREBP-1 (17). Inactivating SREBP-2 in mice results in 100% lethality at a very early stage of embryonic development (10).Mice deficient in only SREB...

Changes in the expression of regulatory enzymes associated with anabolic pathways of energy metabolism in wild and New Zealand rabbits during feed restriction

“…As our liver samples were collected after 5 h of feeding the experimental animals, the ACC1 gene expressions results in WRR group, in which the consequences of feed restriction was more evident, are coherent with the ones obtained by Bruss et al (2010) and Im et al (2009) which can explain the high ACC expression levels in the food restricted rabbits, contrary to what it could be expected.…”

“…The work of Im et al (2009) contributes to an explanation on the metabolic role for the ACC increased gene expression in restricted feed animals. These authors show the effect of ACC2 in liver samples regulating fatty acid synthesis and oxidation during fasting, showing that reduced hepatic ACC2 activity from a deficiency in SREBP-1a, (Sterol regulatory element binding proteins isoform) leads to an unbalanced partitioning of fatty acyl-CoAs between the mitochondrion and the cytosol.…”

“…According to these authors, low ACC2 activity leads to a reduction in malonyl-CoA levels close to the mitochondrial membrane, increasing the activity of the CPT-1 (carnitine palmitoyl/ acyltransferase-1) shuttle system. This effect induces an uncontrolled transport of fatty acyl-CoAs into the mitochondrion, where they are oxidized and converted to excess ketone bodies at the expense of storing the surplus acyl-CoAs in the form of cytosolic triglycerides (Im et al 2009). …”

Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

“…A minor role of SREBP1a in hepatic SREBP-target gene expression had been suggested by the fact that 1a-deficient mice did not show any compromised expression of lipid metabolism genes, with the single exception of a reduced expression of Acacb [28]. In contrast, we here clearly showed by SREBP1a-specific knock-down using exon 1a-specific siRNA that this isoform impacts on the expression of further lipogenic SREBP-target genes in human liver cells.…”

SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism*

“…SREBP-1c has been considered to be central to pathogenesis of metabolic disorders, including fatty liver, and has received much attention as a therapeutic target (15,(21)(22)(23)(43)(44)(45). Small molecules to suppress SREBP-1c acetylation levels by either inhibiting p300 or activating SIRT1 may be useful for treatment of metabolic disorders, such as fatty liver disease, obesity, and type II diabetes.…”