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Specific activation of hypoxia-inducible factor-2 alpha by propionate metabolism via a beta-oxidation-like pathway stimulates MUC2 production in intestinal goblet cellsopen access

Authors
Ma, SeonghoYeom, JiahLim, Young-Hee
Issue Date
11월-2022
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Keywords
Goblet cell; Hypoxia-induced factors; Mucin; beta-Oxidation-like pathway; Propionate
Citation
BIOMEDICINE & PHARMACOTHERAPY, v.155
Indexed
SCIE
SCOPUS
Journal Title
BIOMEDICINE & PHARMACOTHERAPY
Volume
155
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/145461
DOI
10.1016/j.biopha.2022.113672
ISSN
0753-3322
Abstract
Microbiota-derived short-chain fatty acids (SCFAs) are known to stimulate mucin expression in the intestine, which contributes to the gut mucosal immune responses, and the gut mucosal immune system extends to the brain and other organs through several axes. Hypoxia-inducible factors (HIFs), especially HIF-1 alpha, are known to act as the master regulator of mucin expression, however, underlying mechanism of mucin expression during hypoxia by SCFAs remains unclear. In this study, we investigated the mechanism of MUC2 expression by propionate, an SCFA, in intestinal goblet cells. The real time oxygen consumption rate (OCR) and ATPase activity were measured to investigate the induction of hypoxia by propionate. Using 2-dimensional electrophoresis (2 -DE), microarray analysis, and siRNA-induced gene silencing, we found that propionate is metabolized via a beta-oxidation-like pathway instead of the vitamin B-12-dependent carboxylation pathway (also known as the methylmalonyl pathway). We verified the results by analyzing several intermediates in the pathway using LC-MS and GC-MS. Propionate metabolism via the beta-oxidation-like pathway leads to the depletion of oxygen and thereby induces hypoxia. Analysis of HIFs revealed that HIF-2 alpha is the primary HIF whose activation is induced by propionate metabolism in a hypoxic environment and that HIF-2 alpha regulates the expression of MUC2. Thus, hypoxia induced during propionate metabolism via a beta-oxidation-like pathway specifically activates HIF-2 alpha, stimulating MUC2 production in LS 174 T goblet cells. Our findings show that propionate-induced selective HIF-2 alpha stimulation contributes to intestinal mucosal defense.
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보건과학대학 (바이오시스템의과학부)
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