Publisher Correction: Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS (original) (raw)
Related papers
Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS
Nature Communications
We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its bi...
Hepatology Communications, 2019
The global obesity epidemic is driving the concomitant rise in nonalcoholic fatty liver disease (NAFLD). To identify new genes involved in central liver functions, we examined liver RNA‐sequence data from 259 patients who underwent morbidly obese bariatric surgery. Of these patients, 84 had normal liver histology, 40 simple steatosis, 43 nonalcoholic steatohepatitis, and the remaining 92 patients had varying degrees of NAFLD based on liver histology. We discovered oligodendrocyte maturation‐associated long intergenic noncoding RNA (OLMALINC), a long intervening noncoding RNA (lincRNA) in a human liver co‐expression network (n = 75 genes) that was strongly associated with statin use and serum triglycerides (TGs). OLMALINC liver expression was highly correlated with the expression of known cholesterol biosynthesis genes and stearoyl‐coenzyme A desaturase (SCD). SCD is the rate‐limiting enzyme in monounsaturated fatty acids and a key TG gene that is known to be up‐regulated in liver st...
Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis
Nature, 2016
Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux, facilitates cholesterol esterification by promoting fatty acid synthesis, and inhibits cholesterol uptake by the low-density lipoprotein receptor. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (h...
Journal of Clinical Investigation, 1997
The 5 Ј end of the mRNA-encoding sterol regulatory element binding protein-1 (SREBP-1) exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5 Ј exons, each of which is spliced to a common exon 2. Here we show that the ratio of SREBP-1c to 1a transcripts varies markedly among organs of the adult mouse. At one extreme is the liver, in which the 1c transcript predominates by a 9:1 ratio. High 1c:1a ratios are also found in mouse adrenal gland and adipose tissue and in human liver and adrenal gland. At the other extreme is the spleen, which shows a reversed 1c:1a ratio (1:10). In five different lines of cultured cells, including the HepG2 line derived from human hepatocytes, the 1a transcript predominated (1c:1a ratio Ͻ 1:2). In mouse 3T3-L1 preadipocytes, the 1a transcript was present, but the 1c transcript was not detectable. When these cells were differentiated into adipocytes by hormone treatment in culture, the amount of 1a transcript rose markedly (8.2fold), and the 1c transcript remained virtually undetectable. We conclude that the SREBP-1a and 1c transcripts are controlled independently by regulatory regions that respond differentially to organ-specific and metabolic factors. ( J. Clin. Invest. 1997. 99:838-845.) Key words: SREBP-1 • alternative splicing • cholesterol • fatty acids • liver • adipocytes
Biochemical and Biophysical Research Communications, 2007
Ascent to high-altitude results in decreased inspired partial pressure of oxygen because of a decrease in barometric pressure. Altitude acclimatization requires physiological and metabolic changes to improve tolerance to altitude hypoxia. Cellular response to hypoxia results into changes in the profile of gene expression and the present study explored the same in murine model. Liver being the largest metabolic organ, the molecular details of acute hypobaric hypoxia (AHH) induced transcriptional changes in the tissue were investigated. Swiss albino mice were exposed to hypobaric hypoxia ($426 mmHg) in a decompression chamber and cDNA microarray was used to study the transcriptional profile in liver. Notably, by the tenth hour several of the genes involved in sterol metabolism such as SREBF1, INSIG1, HMGCS1, FDFT1, SQLE, and HSD3B4 were downregulated more than 2-fold suggesting that AHH suppresses sterol biosynthesis in the liver. Real-time PCR helped validate the downregulation of SREBF1, HMGCS1, FDFT1, and HSD3B4 genes. However, no significant change was observed in the serum cholesterol levels throughout the AHH exposure. The findings are indicative of transcriptional downregulation of SREBP target genes as a part of acclimatization response to hypoxia. The study highlights the significance of SREBP in the regulation of sterol metabolism under the acute hypoxic response.
Cellular sterol trafficking and metabolism: spotlight on structure
Current Opinion in Cell Biology, 2008
Cholesterol is the main but not the only sterol in cell membranes of higher eukaryotes. Currently, there is an increasing interest toward structurally different sterols, because their membrane partitioning, trafficking, and metabolic properties may differ considerably from those of cholesterol. There is also growing information on specific sterol-protein interactions and their functional consequences, as exemplified by NPC proteins and select ABC-transporters. Several aspects of sterol trafficking and homeostasis are conserved between eukaryotes, and novel, unanticipated findings in this area have recently been made, particularly from genetic screens in yeast. This includes a novel, reversible modification of the sterol structure that affects the choice of transport route.
Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene
The Journal of biological chemistry, 2000
Recent data suggest that sterol regulatory-binding protein (SREBP)-1c plays a key role in the transcriptional regulation of different lipogenic genes mediating lipid synthesis as a key regulator of fuel metabolism. SREBP-1c regulates its downstream genes by changing its own mRNA level, which led us to sequence and analyze the promoter region of the mouse SREBP-1c gene. A cluster of putative binding sites of several transcription factors composed of an NF-Y site, an E-box, a sterol-regulatory element 3, and an Sp1 site were located at -90 base pairs of the SREBP-1c promoter. Luciferase reporter gene assays indicated that this SRE complex is essential to the basal promoter activity and confers responsiveness to activation by nuclear SREBPs. Deletion and mutation analyses suggest that the NF-Y site and SRE3 in the SRE complex are responsible for SREBP activation, although the other sites were also involved in the basal activity. Gel mobility shift assays demonstrate that SREBP-1 binds ...
2020
The purpose of this review is to highlight several areas of lncRNA biology and cancer that we hope will provide some new insights for future research. These include the relationship of lncRNAs and the epithelial to mesenchymal transition (EMT) with a focus on transcriptional and alternative splicing mechanisms and mRNA stability through miRNAs. In addition, we highlight the potential role of enhancer e-lncRNAs, the importance of transposable elements in lncRNA biology, and finally the emerging area of using antisense oligonucleotides(ASOs) and small molecules to target lncRNAs and their therapeutic implications Manuscript Classifications: pointed out several areas need improvement. In case you can address their critiques, we will consider a revised version of it for publication with RNA biology. Reviewer 1: The authors provide a comprehensive review on LncRNA biology and the relationship of lncRNAs and the epithelial to mesenchymal transition (EMT) with a focus on transcriptional and alternative splicing mechanisms and mRNA stability through miRNAs. This review covers well most aspects of lncRNA studies and also talked about the future targeting lncRNAs with ASOs and small molecules. I will only point out some minor revisions that may help this manuscript and the authors can take to improve this review before it is accepted. 1.The modification of RNA is an emerging regulation for RNA biology and the m6A of lncRNA could be an interesting to talk in this review. I recommended the authors can add this to mRNA stability regulation part. We added a section at the very end on EMT and RNA modifications that we felt was more appropriate for this review rather than focusing on the area of mRNA stability. 2. In page8, line 7 of part "LncRNA regulation of miRNAs", the addition semicolon should be deleted.