title: 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.
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612.
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612.
authors.forename: Mira
authors.initials: M
authors.lastname: Yu
authors.affiliation: the Department of Pediatrics, Pusan National University, Yangsan 50612.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Park
authors.affiliation: the Department of Pharmacology, College of Medicine, Seoul National University, Seoul 03080, and.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612,; the Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Busan 46241, Korea. Electronic address: moon@pnu.edu.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D002460:Cell Line; D002784:Cholesterol / Q000172:deficiency*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497325:EGR1 protein, human; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D051766:Early Growth Response Protein 1; D016328:NF-kappa B; D047495:PPAR gamma; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol
keywords: cholesterol regulation; inflammation; intestinal epithelium; intestinal metabolism; intestine; mRNA decay