Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development

Abstract

miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic metabolism with obesity and cancer remains poorly characterized. Herein, we observed that alterations of hepatic miR-22-3p expression with non-alcoholic fatty liver disease (NAFLD) in the context of obesity are not consistent in various human cohorts and animal models in contrast to the well-characterized miR-22-3p downregulation observed in hepatic cancers. To unravel the role of miR-22 in obesity-associated NAFLD, we generated constitutive Mir22 knockout (miR-22KO) mice, which were subsequently rendered obese by feeding with fat-enriched diet. Functional NAFLD- and obesity-associated metabolic parameters were then analyzed. Insights about the role of miR-22 in NAFLD associated with obesity were further obtained through an unbiased proteomic analysis of miR-22KO livers from obese mice. Metabolic processes governed by miR-22 were finally investigated in hepatic transformed cancer cells. Deletion of Mir22 was asymptomatic when mice were bred under standard conditions, except for an onset of glucose intolerance. However, when challenged with a high fat-containing diet, Mir22 deficiency dramatically exacerbated fat mass gain, hepatomegaly, and liver steatosis in mice. Analyses of explanted white adipose tissue revealed increased lipid synthesis, whereas mass spectrometry analysis of the liver proteome indicated that Mir22 deletion promotes hepatic upregulation of key enzymes in glycolysis and lipid uptake. Surprisingly, expression of miR-22-3p in Huh7 hepatic cancer cells triggers, in contrast to our in vivo observations, a clear induction of a Warburg effect with an increased glycolysis and an inhibited mitochondrial respiration. Together, our study indicates that miR-22-3p is a master regulator of the lipid and glucose metabolism with differential effects in specific organs and in transformed hepatic cancer cells, as compared to non-tumoral tissue.

High Glucose Reduces the Paracellular Permeability of the Submandibular Gland Epithelium via the MiR-22-3p/Sp1/Claudin Pathway

“…The long noncoding RNA MIAT is increased in a rat model of diabetic cardiomyopathy and HG-cultured neonatal cardiomyocytes, which upregulates death-associated protein kinase 2 expression by sponging miR-22-3p and consequently leads to cardiomyocyte apoptosis [28]. Moreover, Mir22-knockout mice present dramatically exacerbated fat mass gain, hepatomegaly, and a liver steatosis response to high-fat diet feeding compared to control mice [49]. Although miR-22-3p has been demonstrated to be a master regulator of lipid and glucose metabolism with differential effects on specific organs, its roles in the physiological and pathological processes of the salivary gland remain unknown.…”

Optimization of miR-22 expression cassette for rAAV delivery on diabetes

“…miR-22 is relatively abundant in cells and its overexpression may be difficult compared with those with lower expression levels such as miR-199a [ 20 , 28 – 30 ]. Since the length of pri-miRNA may affect miRNA expression and rAAV has a limited packaging capacity [ 25 , 26 , 31 ], it was necessary to identify the appropriate length of the pri-miR-22.…”

“…The function of miR-22 on insulin sensitivity were controversial [ 16 , 18 – 20 ]. To address this question, we investigated whether miR-22 overexpression affected bodyweight and insulin sensitivity in obese and diabetic mice induced by a high-fat diet (HFD).…”

“…Additionally, it was reported that miR-22 deficiency did not affect the glucose tolerance and insulin resistance in mice fed a HFD [ 19 ]. However, another study showed that miR-22 deletion in mice increased the bodyweight and fat accumulation, and deteriorated glucose intolerance and insulin resistance under HFD condition [ 20 ]. It was also noted that miR-22 is one of the most abundant miRs in the liver [ 20 ], which could make it difficult to be overexpressed.…”

Preparation and Characterization of Silymarin-Conjugated Gold Nanoparticles with Enhanced Anti-Fibrotic Therapeutic Effects against Hepatic Fibrosis in Rats: Role of MicroRNAs as Molecular Targets

“…In line with this data, miR-22 was down-regulated in liver samples from patients with liver fibrosis or cirrhosis [ 81 ]. Also, Gjorgjieva and her co-workers have found that deficiency of miR-22 dramatically aggravated fat mass accumulation, hepatomegaly, and liver steatosis in mice [ 82 ]. The computational analysis suggested TGFβR1 as a potential target of miR-22 which was confirmed in the present study by the marked up-regulation of TGFβR1 in CCl 4 -rats (about 5.5- Fold) and the strong negative correlation between the hepatic expression of miR-22 and TGFβR1 mRNA.…”