Epigenetic influence of long non-coding RNAs on the development of insulin resistance in metabolically associated fatty liver disease (part 2)

Understanding the mechanisms of action of long non-coding RNAs (lncR) and their significance in the development of insulin resistance (IR) in patients with metabolically associated fatty liver disease will allow modifying and increasing the effectiveness of methods for diagnosing and treating metabolic disorders. Adipose tissue is insulin-dependent and plays a significant role in glucose metabolism. The stimulation of the insulin receptor (INSR) of white adipose tissue adipocytes activates the transport of glucose, free fatty acids (FFA), and glycerol into the cell, stimulates lipogenesis de novo and adipogenesis, and also inhibits the activity of lipolysis mechanisms. The leading triggers that cause the development of IR in adipocytes are lipotoxicity and low-grade inflammation of adipose tissue. In particular, in the adipose tissue of patients with metabolically associated steatohepatitis, overexpression of TNF-α and IL-6 mRNA is observed. Inflammatory mediators such as TNF-α and IL-1β inhibit INSR, and TNF-α induces phosphorylation of the serine residue of the IRS-1 molecule, disrupting signal transmission to phosphatidylinositol-4,5-bisphosphate-3-kinase. Obesity activates mitochondrial FFA-stimulated adenine nucleotide translocase 2, which leads to hypoxia of adipocytes and stimulates hypoxia-induced factor-1α. Activation of the latter causes inhibition of glucose uptake by adipocytes, enhances the process of glycolysis by affecting numerous enzymes involved in glucose metabolism, also inducing dysfunction and inflammation of adipose tissue. The authors emphasize that insulin-resistant adipose tissue is characterized by a low level of glucose influx into adipocytes, a high level of FFA release after insulin stimulation, which generally leads to hyperglycemia and hyperlipidemia. The following lncRs are involved in the pathogenesis of IR of white adipose tissue: ADIPINT, ASMER, Blnc1, DIO3OS, GAS5, Gm15290, H19, LncOb, MEG3, SRA. Long non-coding RNAs involved in the pathogenesis of IR of muscle tissue are IRLnc, H19, NONMMUT044897.