AUF-1 knockdown in mice undermines gut microbial butyrate-driven 
hypocholesterolemia through AUF-1–Dicer-1–mir-122 hierarchy

Das, O; Kundu, J; Ghosh, A; Gautam, A; Ghosh, S; Chakraborty, M; Masid, A; Gauri, SS; Mitra, D; Dutta, M; Mukherjee, B; Sinha, S; Bhaumik, M

doi:10.3389/fcimb.2022.1011386

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AUF-1 knockdown in mice undermines gut microbial butyrate-driven hypocholesterolemia through AUF-1–Dicer-1–mir-122 hierarchy

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Gautam, A
IMPRS From Molecules to Organisms, Max Planck Institute for Biology Tübingen, Max Planck Society;

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引用

Das, O., Kundu, J., Ghosh, A., Gautam, A., Ghosh, S., Chakraborty, M., Masid, A., Gauri, S., Mitra, D., Dutta, M., Mukherjee, B., Sinha, S., & Bhaumik, M. (2022). AUF-1 knockdown in mice undermines gut microbial butyrate-driven hypocholesterolemia through AUF-1–Dicer-1–mir-122 hierarchy. Frontiers in Cellular and Infection Microbiology, 12:. doi:10.3389/fcimb.2022.1011386.

引用: https://hdl.handle.net/21.11116/0000-000C-19D9-4

要旨

Introduction and objective: Cholesterol homeostasis is a culmination of cellular synthesis, efflux, and catabolism to important physiological entities where short chain fatty acid, butyrate embodied as a key player. This discourse probes the mechanistic molecular details of butyrate action in maintaining host-cholesterol balance.
Methods: Hepatic mir-122 being the most indispensable regulator of cholesterol metabolic enzymes, we studied upstream players of mir-122 biogenesis in the presence and absence of butyrate in Huh7 cells and mice model. We synthesized unique self-transfecting GMO (guanidinium-morpholino-oligo) linked PMO (Phosphorodiamidate-Morpholino Oligo)-based antisense cell-penetrating reagent to selectively knock down the key player in butyrate mediated cholesterol regulation.
Results: We showed that butyrate treatment caused upregulation of RNA-binding protein, AUF1 resulting in RNase-III nuclease, Dicer1 instability, and significant diminution of mir-122. We proved the importance of AUF1 and sequential downstream players in AUF1-knock-down mice. Injection of GMO-PMO of AUF1 in mouse caused near absence of AUF1 coupled with increased Dicer1 and mir-122, and reduced serum cholesterol regardless of butyrate treatment indicating that butyrate acts through AUF1.
Conclusion: The roster of intracellular players was as follows: AUF1-Dicer1-mir-122 for triggering butyrate driven hypocholesterolemia. To our knowledge this is the first report linking AUF-1 with cholesterol biogenesis.