Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients’ blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
Lipid homeostasis in vertebrates is regulated by 3 sterol regulatory element binding protein (SREBP) isoforms. Here, we identify targets of SREBP-1 in mammalian liver using chromatin immunoprecipitation-high-throughput DNA sequencing. Antisera to SREBP-1 were used with liver chromatin from mice fed a high-carbohydrate diet after a fast, which leads to superinduction of hepatic SREBP-1c expression. SREBP-1-DNA complexes were subjected to massive parallel DNA sequencing using the Illumina Genome Analyzer II, resulting in 5.7 million sequence reads. Mapping these reads to the mouse reference genome identified 426 peaks of SREBP-1 binding vs. a control antibody. These binding peaks show a striking enrichment in proximal promoter regions, with 52% located within 1 kb upstream of a transcription start site. A previously undescribed sequence motif (5-ACTACANNTCCC-3) was present in 76% of the total peaks, and we show that it is a functional SREBP-1 response element. Our analysis also reveals that an Sp1 consensus site is present as a ''coregulatory'' motif in 50% of the SREBP-1 binding peaks, consistent with previous functional studies. SREBP-1 bound not only to many well-characterized SREBP-1 target genes but to several other previously unknown targets in lipid and carbohydrate metabolism as well as many putative target genes in other diverse biological pathways.ChIP-seq ͉ fasting/refeeding ͉ Sp1 ͉ Kolmogorov-Smirnov test A ll living organisms have evolved strategic regulatory systems to coordinate metabolic flux into potentially competing biochemical pathways to manage metabolite and end-product pools for optimal cellular fitness. This is particularly important in mammalian lipid homeostasis because cholesterol and fatty acids, the 2 major classes of mammalian lipids, are key to the structure and function of all cells, and unbalanced flux into these pathways can be both energy-inefficient and toxic. In vertebrates, lipid homeostasis is maintained in part by sterol regulatory element binding protein (SREBP) transcription factors, which are synthesized as Ϸ125-kDa precursors containing 2 membrane-spanning domains that localize the immature proteins to the endoplasmic reticulum membrane (1).Overlapping transcripts from 1 gene encode SREBP-1a and SREBP-1c isoforms, and the singular SREBP-2 is encoded from a distinct unlinked gene (2). There is an intricate system of nutrient sensing that relates cellular levels of cholesterol and other key lipid components to the expression and multistep membrane trafficking/protease pathway that converts the membrane-bound SREBPs into the much smaller nuclear targeted transcription factors.SREBPs activate genes encoding most of the key enzymes in cholesterol and fatty acid metabolism (3); thus, coupling SREBP processing to pathway flux provides a direct link between the activity of the regulatory factors and metabolic demand. Overexpression and targeted elimination studies in mice have produced crucial information on the roles of SREBPs in lipid regulation (3).The available evidence indi...
NFκB is a central mediator of inflammation. Present inhibitors of NFκB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFκB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFκB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFκB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFκB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFκB enhanceosome offers a promising target for useful anti-inflammatory agents.
The assembly of ZnO nanoparticles into nanogap electrodes using ac dielectrophoresis (DEP) process is reported. DEP parameters such as frequency, voltage, and time were optimized to assemble minimum number of nanoparticles into nanogap electrodes. Frequency variation study revealed that positive DEP is active at frequencies less than 500 kHz; whereas negative DEP starts dominating at 1 MHz. The fabricated device exhibited a nonlinear I-V characteristic and under ultraviolet (UV) illumination a remarkable change in conductivity of one order of magnitude was observed. The results show the potential for realizing future optoelectronic devices such as miniaturized UV sensor.
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