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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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/6/2979 |
| _version_ | 1797470980870766592 |
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| author | Mai Thi Nguyen Kyung-Ho Min Wan Lee |
| author_facet | Mai Thi Nguyen Kyung-Ho Min Wan Lee |
| author_sort | Mai Thi Nguyen |
| collection | DOAJ |
| 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 <i>IRS-1</i>, 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 <i>IRS-1</i> 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. |
| first_indexed | 2024-03-09T19:43:05Z |
| format | Article |
| id | doaj.art-1b501217ec4b45ad90bbb9fa24702256 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:43:05Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1b501217ec4b45ad90bbb9fa247022562023-11-24T01:30:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236297910.3390/ijms23062979MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in HepatocytesMai Thi Nguyen0Kyung-Ho Min1Wan Lee2Department of Biochemistry, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, KoreaDepartment of Biochemistry, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, KoreaDepartment of Biochemistry, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, KoreaExcessive 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 <i>IRS-1</i>, 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 <i>IRS-1</i> 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.https://www.mdpi.com/1422-0067/23/6/2979miR-183-5pIRS-1insulin resistanceobesity |
| spellingShingle | Mai Thi Nguyen Kyung-Ho Min Wan Lee MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes International Journal of Molecular Sciences miR-183-5p IRS-1 insulin resistance obesity |
| 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 | miR-183-5p IRS-1 insulin resistance obesity |
| url | https://www.mdpi.com/1422-0067/23/6/2979 |
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