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조회396

김주일Juil Kim

부산대학교

Theranostics, Published 2024-1-20, 14 (3) | https://doi.org/10.7150/thno.88586 Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction

Juil Kim^1,#, Hoyoung Jeong^1,#, Navin Ray¹, Ki-Hyung Kim^1,2,3, Yuseok Moon^1,3,4,*

¹Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea.

²Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Pusan National University, Busan, Korea.

³Biomedical Research Institute, Pusan National University, Busan, Korea.

⁴Graduate Program of Genomic Data Sciences, Pusan National University, Yangsan 50612, Korea.

^#Authors equally contributed to the present study.

^*Corresponding author: Yuseok Moon

Abstract

Rationale: The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health. In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming. We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes. Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation. Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity. The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells. The lipidomic profiling was performed to address RIS-induced intracellular fat alterations. Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells. Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice. Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated. In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor ( LDLR) via both transcriptional and post-transcriptional regulation. Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress. Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation- and obesity-associated gut model. Conclusion: The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-02-13)
연구진국내 연구진
분야 의약학 > 인체시스템의학

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