Abstract
Insulin resistance has been implicated in alcoholic liver disease. A previous study has shown that microRNAs (miRNAs) play a major role in the production, secretion, and function of insulin. MiRNAs are capable of repressing multiple target genes that in turn negatively regulate various physiological and pathological activities. However, current information on the biological function of miRNAs in insulin resistance is limited. The goal of the present study was to elucidate the role of miR-378b in alcohol-induced hepatic insulin resistance and its underlying mechanism. This study has observed that miR-378b is up-regulated in National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcoholic mouse models as well as in ethanol-induced L-02 cells in vitro. Furthermore, miR-378b overexpression impaired the insulin signaling pathway, and inhibition of miR-378b improved insulin sensitivity in vivo and in vitro. A mechanistic study revealed that IR and p110α are direct targets of miR-378b. Together, these results suggest that miR-378b controls insulin sensitivity by targeting the insulin receptor (IR) as well as p110α and possibly play an inhibitory role in the development of insulin resistance, thereby providing insights into the development of novel diagnostic and treatment methods.
Highlights
Alcoholic liver disease (ALD) is a common liver disorder with high global morbidity and mortality rates (Ramaiah et al, 2004)
The results clearly showed that glucose tolerance and insulin tolerance were impaired, and hyperglycemia developed in EtOHfed mice, which are the characteristics of insulin resistance (Figures 1H–J)
Because this study was centered on miRNAs that are related to ethanol-induced insulin resistance, we employed ethyl alcohol (EtOH)-fed mice in identifying miRNAs that are modulated by alcohol. quantitative real-time (qRT)-PCR analysis showed that miR378b expression in the model mice was over three-fold greater than that in control diet (CD)-fed mice (Figure 1K)
Summary
Alcoholic liver disease (ALD) is a common liver disorder with high global morbidity and mortality rates (Ramaiah et al, 2004). One of the most important organs for insulin action is the liver. Insulin resistance plays a pivotal role in the formation of ALD (Magdaleno et al, 2017; Chen et al, 2018). Excessive alcohol uptake increases the risk for insulin resistance, which is characterized by the inability of insulin-sensitive tissues to respond to insulin, resulting in various metabolic syndromes (Aberg et al, 2018; Tatsumi et al, 2018). Alcohol overconsumption may promote the pathogenesis of hepatic insulin resistance by inhibiting insulin signaling (Carr and Correnti, 2015). Hepatic steatosis induced by alcohol leads to intracellular metabolic imbalance, can promote insulin resistance in liver cells
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