MicroRNA-411-5p alleviates hepatic insulin resistance via suppressing transcription factor Sp2 in MASLD mice.

Abstract

Insulin resistance is often characterized as the factor that contributes to the emergence of metabolic diseases. Hepatic microRNAs (miRNAs) played critical roles in the development of metabolic-associated steatotic liver disease (MASLD) and insulin resistance. To investigate the effects of hepatic miR-411-5p in regulating insulin resistance, the present study utilized primary mouse hepatocytes and mice with MASLD. Suppression of miR-411-5p decreased hepatocyte glycogen production and phosphorylation of AKT, but miR-411-5p mimic improved insulin sensitivity. Mechanistically, 3'-UTR of transcription factor Sp2 was one of binding sites of miR-411-5p. Treatment of miR-411-5p mimic suppressed the Sp2 mRNA and protein levels, enhancing the insulin signaling activity in the primary mouse hepatocytes. Hepatocyte-specific overexpression of Sp2 induced hepatic lipid accumulation and activation of related metabolic pathways. On the contrast, inhibition of miR-411-5p reversely upregulated the expression of Sp2, and exaggerated the insulin resistance in primary hepatocytes and mouse model. Similarly, miR-411-5p mimic decreased obesity-induced hyperinsulinemia, glucose intolerance, insulin intolerance, and pyruvate intolerance. Furthermore, the parameters of MASLD, including lipid deposits, inflammation and fibrosis, were improved after miR-411-5p replenishment, but co-administration with adeno-associated virus (AAV)-Sp2 abolished these benefits in obese mouse model. Taken together, these findings demonstrated that Sp2-dependent miR-411-5p action regulates insulin resistance and MASLD, which provides therapeutic approach toward resolving insulin resistance.