Summary We show mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of Caspase-1 and secretion of IL-1β. We show that SREBP-1a not only activates genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens.

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...

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A 12‐week choline intervention study was conducted to investigate the effects of pregnancy and choline intake on the fate of orally consumed choline. Healthy non‐pregnant (n = 21) and pregnant women (n=27, 27wk gestation) were randomized to controlled choline intakes of either 450 (choline AI) or 900 mg/day; 350 mg/day dietary choline and either 100 or 550 mg/d supplemental choline chloride. During the last six weeks of the study, ~20% of the total choline intake was provided as deuterium labeled choline (d9‐choline). The labeling of choline and its metabolites was examined at the end of the study (wk 12) in plasma and urine. Pregnancy affected the use of dietary choline with higher concentrations of plasma d9‐choline (P = 0.008), lower concentrations of plasma d6‐dimethylglycine (d6‐DMG) (P < 0.001), and higher urinary d9‐choline excretion (P = 0.001) in pregnant women. A higher choline intake (900 vs 450 mg/d) yielded higher plasma concentrations of d9‐choline (P = 0.003), d6‐DMG (P = 0.02), and d‐9 betaine (especially in pregnant women; P= 0.002 for choline x pregnancy) as well as greater urinary d6‐DMG excretion (P = 0.006). These data show that (i) pregnancy alters the use of orally consumed choline and (ii) a choline intake level exceeding the choline AI increases the availability of labile methyl groups for one‐carbon metabolic reactions especially in pregnant women. Supported by grants from the USDA, ENC, and NCBA.