No abstract

Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcriptionstimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipidlowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70 -90% of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of 125 I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.sterol regulatory element-binding proteins ͉ cholesterol ͉ fatty acids ͉ knockout mice T he proteolytic release of sterol regulatory element-binding proteins (SREBPs) from cell membranes stimulates lipid synthesis in hepatocytes and other cells. Inhibition of this proteolytic release in liver might lead to reduced lipid synthesis and reduced lipid accumulation in liver, blood, and other organs. The consequences of blocking hepatic SREBP proteolysis can now be investigated as a result of the recent molecular identification of the proteins that mediate this process (1).SREBPs are synthesized as membrane-bound precursors of Ϸ1,150 aa in length (1). The NH 2 terminal domain of Ϸ480 aa is a transcription factor of the basic helix-loop-helix leucine zipper family. This domain is followed by a hairpin membraneattachment domain of Ϸ80 aa, which consists of two transmembrane helices separated by a short 30-aa hydrophilic loop that projects into the lumen of the endoplasmic reticulum. The COOH-terminal domain of Ϸ590 aa faces the cytosol where it performs a regulatory function.Immediately after their synthesis, SREBPs form complexes with SREBP cleavage-activating protein (SCAP), an endoplasmic reticulum protein that contains eight membrane-spanning helices followed by a cytoplasmic domain of 545 aa (2).

If neuropilin-2 and the growth factor VEGF-C don’t come together, lymphatic vessels don’t branch apart.

Investigating microbial response to environmental variables is of great importance for understanding of microbial acclimatization and evolution in natural environments. However, little is known about how microbial communities responded to environmental factors (e.g. salinity, geographic distance) in lake surface sediments of the Qinghai-Tibetan Plateau (QTP). In this study, microbial diversity and community structure in the surface sediments of nine lakes on the QTP were investigated by using the Illumina Miseq sequencing technique and the resulting microbial data were statistically analyzed in combination with environmental variables. The results showed total microbial community of the studied lakes was significantly correlated (r = 0.631, P < 0.001) with lake salinity instead of geographic distance. This suggests that lake salinity is more important than geographic distance in shaping the microbial diversity and community structure in the studied samples. In addition, the abundant and rare taxa (OTUs with relative abundance higher than 1% and lower than 0.01% within one sample, respectively) were significantly (P < 0.05) correlated (r = 0.427 and 0.783, respectively) with salinity, suggesting rare taxa might be more sensitive to salinity than their abundant counterparts, thus cautions should be taken in future when evaluating microbial response (abundant vs. rare sub-communities) to environmental conditions.