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MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes

Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signal...

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Autores principales: Nguyen, Mai Thi, Min, Kyung-Ho, Lee, Wan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953084/
https://www.ncbi.nlm.nih.gov/pubmed/35328400
http://dx.doi.org/10.3390/ijms23062979
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author Nguyen, Mai Thi
Min, Kyung-Ho
Lee, Wan
author_facet Nguyen, Mai Thi
Min, Kyung-Ho
Lee, Wan
author_sort Nguyen, Mai Thi
collection PubMed
description Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signaling and sensitivity are largely unknown. Here, we investigated the role of SFA-induced miR-183-5p in the regulation of proximal insulin signaling molecules and the development of hepatic insulin resistance. HepG2 hepatocytes treated with palmitate and the livers of high-fat diet (HFD)-fed mice exhibited impaired insulin signaling resulting from dramatic reductions in the protein expressions of insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1). Differential expression analysis showed the level of miR-183-5p, which tentatively targets the 3′UTR of IRS-1, was significantly elevated in palmitate-treated HepG2 hepatocytes and the livers of HFD-fed mice. Dual-luciferase analysis showed miR-183-5p bound directly to the 3′UTR of IRS-1 and reduced IRS-1 expression at the post-transcriptional stage. Moreover, transfection of HepG2 hepatocytes with miR-183-5p mimic significantly inhibited IRS-1 expression and hindered insulin signaling, consequently inhibiting insulin-stimulated glycogen synthesis. Collectively, this study reveals a novel mechanism whereby miR-183-5p induction by SFA impairs insulin signaling and suggests miR-183-5p plays a crucial role in the pathogenesis of hepatic insulin resistance in the background of obesity.
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spelling pubmed-89530842022-03-26 MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes Nguyen, Mai Thi Min, Kyung-Ho Lee, Wan Int J Mol Sci Article Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signaling and sensitivity are largely unknown. Here, we investigated the role of SFA-induced miR-183-5p in the regulation of proximal insulin signaling molecules and the development of hepatic insulin resistance. HepG2 hepatocytes treated with palmitate and the livers of high-fat diet (HFD)-fed mice exhibited impaired insulin signaling resulting from dramatic reductions in the protein expressions of insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1). Differential expression analysis showed the level of miR-183-5p, which tentatively targets the 3′UTR of IRS-1, was significantly elevated in palmitate-treated HepG2 hepatocytes and the livers of HFD-fed mice. Dual-luciferase analysis showed miR-183-5p bound directly to the 3′UTR of IRS-1 and reduced IRS-1 expression at the post-transcriptional stage. Moreover, transfection of HepG2 hepatocytes with miR-183-5p mimic significantly inhibited IRS-1 expression and hindered insulin signaling, consequently inhibiting insulin-stimulated glycogen synthesis. Collectively, this study reveals a novel mechanism whereby miR-183-5p induction by SFA impairs insulin signaling and suggests miR-183-5p plays a crucial role in the pathogenesis of hepatic insulin resistance in the background of obesity. MDPI 2022-03-10 /pmc/articles/PMC8953084/ /pubmed/35328400 http://dx.doi.org/10.3390/ijms23062979 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nguyen, Mai Thi
Min, Kyung-Ho
Lee, Wan
MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title_full MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title_fullStr MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title_full_unstemmed MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title_short MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes
title_sort mir-183-5p induced by saturated fatty acids hinders insulin signaling by downregulating irs-1 in hepatocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953084/
https://www.ncbi.nlm.nih.gov/pubmed/35328400
http://dx.doi.org/10.3390/ijms23062979
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