Epithelial Cholesterol Deficiency Attenuates Human Antigen R-linked Pro-inflammatory Stimulation via an SREBP2-linked Circuit

Abstract

Patients with chronic intestinal ulcerative diseases, such as inflammatory bowel disease, tend to exhibit abnormal lipid profiles, which may affect the gut epithelial integrity. We hypothesized that epithelial cholesterol depletion may trigger inflammation-checking machinery via cholesterol sentinel signaling molecules whose disruption in patients may aggravate inflammation and disease progression. In the present study, sterol regulatory element-binding protein 2 (SREBP2) as the cholesterol sentinel was assessed for its involvement in the epithelial inflammatory responses in cholesterol-depleted enterocytes. Patients and experimental animals with intestinal ulcerative injuries showed suppression in epithelial SREBP2. Moreover, SREBP2-deficient enterocytes showed enhanced pro-inflammatory signals in response to inflammatory insults, indicating regulatory roles of SREBP2 in gut epithelial inflammation. However, epithelial cholesterol depletion transiently induced pro-inflammatory chemokine expression regardless of the well known pro-inflammatory nuclear factor-κB signals. In contrast, cholesterol depletion also exerts regulatory actions to maintain epithelial homeostasis against excessive inflammation via SREBP2-associated signals in a negative feedback loop. Mechanistically, SREBP2 and its induced target EGR-1 were positively involved in induction of peroxisome proliferator-activated receptor γ (PPARγ), a representative anti-inflammatory transcription factor. As a crucial target of the SREBP2-EGR-1-PPARγ-associated signaling pathways, the mRNA stabilizer, human antigen R (HuR) was retained in nuclei, leading to reduced stability of pro-inflammatory chemokine transcripts. This mechanistic investigation provides clinical insights into protective roles of the epithelial cholesterol deficiency against excessive inflammatory responses via the SREBP2-HuR circuit, although the deficiency triggers transient pro-inflammatory signals.

Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination

“…Fdft1 is a gene encoding for squalene synthase (SQS), which is the first enzyme in the committed cholesterol biosynthesis pathway (Figure 2a). In contrast to previous findings (Memon et al., 1997; Park et al., 2016), neither Srebf2 (Figure 3e) nor Fdft1 (Figure 3f) mRNA levels were decreased in cytokine‐treated gmASTRs and wmASTRs. Instead, transcripts of both Fdft1 and Srebf2 seemed to increase in cytokine‐treated gmASTRs and wmASTRs, indicating a potential compensatory mechanism for the decreased cholesterol efflux from both types of ASTRs.…”

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

“…For example, immune pathway and cholesterol metabolism and homeostasis involve many of the same genes including ApoE, TREM2 and ABCA7. Recent studies suggested SREBP‐2 as a signaling hub integrating cholesterol metabolism with NLRP3 inflammasome assembly and inflammation activation , while SREBP‐2‐deficiency could also enhance pro‐inflammatory signals in response to inflammatory insults . Thus, SREBP‐2 dysregulation downstream to tau alterations could potentially cause broader detrimental effects than cholesterol dis‐homeostasis and amplify toxic effects of tau through additional pathways such as neuroinflammation.…”

1α,25(OH)2D3 alleviates high glucose–induced lipid accumulation in rat renal tubular epithelial cells by inhibiting SREBPs

“…22 Then m-SREBP migrates into the nucleus to activate its downstream genes involved in lipid biosynthesis as well as uptake. 23,24,44 The study by Cheng et al 45 reveals that the glycosylation of SCAP induced by glucose resulted in lipid accumulation in cancer cells. We did not check glycosylation of SCAP in NRK-52E cells.…”