Propionate stimulates MUC2 expression through metabolism of β-oxidation-like pathway that boosts mitochondrial respiration and resultant induction of HIF-2α activation

Microbiota-derived short chain fatty acids (SCFAs) are one of the hottest issues for its various bioactivities in the gut, immune system extending to brain or other organs through several axises. Though many intensive studies have been implementing til recent, some parts among a plenty of actions occurred in the gut solely are unrevealed so as their mechanism. Propionate, one of the representative SCFAs with butyrate is basically known for its inhibiting activity of histone deacetylation (HDAC) and stimulation of mucin expression in mucosae. However, the mechanism of the stimulating action needs to be elucidated in more detail and understandable way. Here, we firstly investigated the effect of propionate on expression of MUC2, one of the main subtype mucin, in goblet cell line LS 174T and suggest a mechanism of the action along the order of events, linked to metabolic shift. Propionate at the concentration of 1 mM to 4 mM induced the expression of MUC2 gradually in the transcriptional- and protein level at 24 h. At the initial parts of treatment of propionate, the odd SCFA was metabolized along vitamin B12-independent β-oxidation-like pathway and the metabolism led cells to boost mitochondrial respiration until 18 h after treatment. However, another possible metabolism pathway, vitamin B12-dependent carboxylation pathway was not involved to the resulted action. At the latter parts, the master regulator of hypoxia, Hypoxia-induced factors (HIFs) were fluctuated respectively and among them, activated HIF-2α was identified to regulate the expression level of MUC2. In summary, propionate might induce β-oxidation-like pathway at the initial part so that mitochondrial respiration is upregulated. In an effort of LS 174T to adapt to naturally formed hypoxia by response to propionate, each activity of HIF subtypes was regulated in a way of entangled to each other and activated HIF-2α stimulated MUC2 expression.