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

Monika Gjorgjieva,Serge Nef,Christine Maeder,Dorothea Portius,Alexander Adibekian,Xavier Montet,Anne-Sophie Ay,Marta Correia De Sousa,Margot Fournier,Didier Picard,Daniel Abegg,Pia Rantakari,Matti Poutanen,Michelangelo Foti,Flavien Berthou,Cyril Sobolewski,Fu-Ping Zhang

doi:10.3390/jpm10040170

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.

Highlights

Obesity and the metabolic syndrome are associated with a spectrum of hepatic pathologies classically defined as non-alcoholic fatty liver disease (NAFLD) or, as suggested more recently, as metabolic dysfunction-associated fatty liver disease (MAFLD)
In order to assess the potential roles of miR-22-3p in metabolic disorders associated with NAFLD/obesity, we first cross-referenced common predicted/validated miR-22-3p targets between mice and human, which were further compared with gene lists associated to glucose and lipid metabolism (Figure 1A,B)
Our in vitro data converge to different conclusions about the role of miR-22 in hepatic human cancer cells, since miR-22 expression led to a classical Warburg-like effect [26], by increasing glycolysis and decreasing mitochondrial respiration rates

Summary

Introduction

Obesity and the metabolic syndrome are associated with a spectrum of hepatic pathologies classically defined as non-alcoholic fatty liver disease (NAFLD) or, as suggested more recently, as metabolic dysfunction-associated fatty liver disease (MAFLD). These hepatic metabolic disorders start with an excessive accumulation of lipids in the hepatocytes (steatosis). Chronic accumulation of fat in hepatocytes disrupts with time the normal hepatic homeostasis through abnormal molecular signaling, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and hepatocyte death These insults elicit, on a long term, a chronic inflammatory response leading to non-alcoholic steatohepatitis (NASH) and favoring hepatic fibrogenesis. An end-stage of these hepatic disorders is the further development of hepatocellular carcinoma (HCC), which mostly arises in cirrhotic livers, but which can occur with NASH/fibrosis only [1,2]

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