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Zhu, Mengyu; Wei, Yuanyuan; Geissler, Claudia; Abschlag, Kathrin; Campos, Judit Corbalan; Hristov, Michael; Möllmann, Julia; Lehrke, Michael; Karshovska, Ela; Schober, Andreas (2017): Hyperlipidemia-Induced MicroRNA-155-5p Improves beta-Cell Function by Targeting Mafb. In: Diabetes, Vol. 66, No. 12: pp. 3072-3084
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A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon like peptide 1 (GLP-1)-mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic beta-cells, which improved glucosemetabolism and the adaptation of beta-cells to obesityinduced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes beta-cell function through IL-6-induced GLP-1 production in alpha-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in beta-cells by hyperlipidemia-associated endotoxemia improves the adaptation of beta-cells to insulin resistance and represents a protective mechanism in the islet stress response.