MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies

Simino, Laís Angélica de Paula; Panzarin, Carolina; Fontana, Marina Figueiredo; Fante, Thaís de; Geraldo, Murilo Vieira; Ignácio-Souza, Letícia Martins; Milanski, Marciane; Torsoni, Márcio Alberto; Ross, Michael G.; Desai, Mina; Torsoni, Adriana Souza

doi:10.1038/s41598-021-88518-8

Cited by 24 publications

(31 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Suppression of G-subunit gene expression can suppress the activity of the AMPK complex. In the work of Simino et al (2021) , Prkaa2 (AMPKα2) was shown to be a direct let-7 target in the liver in a steatosis model ( Simino et al, 2021 ). In general, a decrease in the expression of AMPK complex genes by RNA-dependent epigenetic regulation indicates dysfunction of the complex, consistent with data from other researchers.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

Vulf

Skuratovskaia

Komar

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis—two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Differentially Expressed Mirnas Alter Energy Balance In the Liver By Targeting Genes Of The Ampk Complexmentioning

confidence: 99%

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

Vulf

Skuratovskaia

Komar

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Recently, there has been evidence that the expression of Let-7 is linked to glucose metabolism and insulin levels during pregnancy. Furthermore, Let-7 -mediated AMPK contributes to liver metabolism [ 151 ]. Additionally, Zhong et al revealed that one diabetes-related drug, metformin, increases AMPL activity and Let-7 to regulate gene methylation in ARK2 and MCF-7 cells [ 152 ].…”

Section: Possible Connections Between Let-7 -Mediated Glycolysis and Autophagy In Cancer Progressionmentioning

confidence: 99%

The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression

Liao

2021

IJMS

View full text Add to dashboard Cite

Cancer is usually a result of abnormal glucose uptake and imbalanced nutrient metabolization. The dysregulation of glucose metabolism, which controls the processes of glycolysis, gives rise to various physiological defects. Autophagy is one of the metabolic-related cellular functions and involves not only energy regeneration but also tumorigenesis. The dysregulation of autophagy impacts on the imbalance of metabolic homeostasis and leads to a variety of disorders. In particular, the microRNA (miRNA) Let-7 has been identified as related to glycolysis procedures such as tissue repair, stem cell-derived cardiomyocytes, and tumoral metastasis. In many cancers, the expression of glycolysis-related enzymes is correlated with Let-7, in which multiple enzymes are related to the regulation of the autophagy process. However, much recent research has not comprehensively investigated how Let-7 participates in glycolytic reprogramming or its links to autophagic regulations, mainly in tumor progression. Through an integrated literature review and omics-related profiling correlation, this review provides the possible linkage of the Let-7 network between glycolysis and autophagy, and its role in tumor progression.

show abstract

“…NAFLD is defined as an ectopic lipid accumulation within the hepatocytes up to 5% in the absence of drugs or alcohol consumption ( Lindenmeyer and McCullough, 2018 ), which can progress to stages with associated inflammation and fibrosis, fatally causing liver failure ( Koppe, 2014 ; Bellentani and Med Stefano Bellentani, 2017 ). Recent studies have demonstrated that NAFLD development can be triggered during fetal and early stages of life, as a consequence of exposure to a maternal obesogenic environment, such as a high-fat diet (HFD) consumption ( Hoover et al, 1987 ; Fernandez-Twinn et al, 2015 ; Simino et al, 2021 ). In addition, the HFD consumption by dams predisposes offspring to higher body weight and adiposity, dyslipidemia, and insulin resistance at different stages of life ( Melo et al, 2014 ; Fante et al, 2016 ; Lemes et al, 2018 ; Castro-Rodríguez et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the HFD consumption by dams predisposes offspring to higher body weight and adiposity, dyslipidemia, and insulin resistance at different stages of life ( Melo et al, 2014 ; Fante et al, 2016 ; Lemes et al, 2018 ; Castro-Rodríguez et al, 2021 ). The development of these metabolic abnormalities in the offspring, as well as NAFLD, has shown to be under epigenetic control ( Benatti et al, 2014 ; Fernandez-Twinn et al, 2015 ; Bianco-Miotto et al, 2017 ; Simino et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity

Simino

Fontana

Fante

et al. 2022

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Obesity has become a public health problem in recent decades, and during pregnancy, it can lead to an increased risk of gestational complications and permanent changes in the offspring resulting from a process known as metabolic programming. The offspring of obese dams are at increased risk of developing non-alcoholic fatty liver disease (NAFLD), even in the absence of high-fat diet consumption. NAFLD is a chronic fatty liver disease that can progress to extremely severe conditions that require surgical intervention with the removal of the injured tissue. Liver regeneration is necessary to preserve organ function. A range of pathways is activated in the liver regeneration process, including the Hippo, TGFβ, and AMPK signaling pathways that are under epigenetic control. We investigated whether microRNA modulation in the liver of the offspring of obese dams would impact gene expression of Hippo, TGFβ, and AMPK pathways and tissue regeneration after partial hepatectomy (PHx). Female Swiss mice fed a standard chow or a high-fat diet (HFD) before and during pregnancy and lactation were mated with male control mice. The offspring from control (CT-O) and obese (HF-O) dams weaned to standard chow diet until day 56 were submitted to PHx surgery. Prior to the surgery, HF-O presented alterations in miR-122, miR-370, and Let-7a expression in the liver compared to CT-O, as previously shown, as well as in its target genes involved in liver regeneration. However, after the PHx (4 h or 48 h post-surgery), differences in gene expression between CT-O and HF-O were suppressed, as well as in microRNA expression in the liver. Furthermore, both CT-O and HF-O presented a similar regenerative capacity of the liver within 48 h after PHx. Our results suggest that survival and regenerative mechanisms induced by the partial hepatectomy may overcome the epigenetic changes in the liver of offspring programmed by maternal obesity.

show abstract

MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies

Cited by 24 publications

References 26 publications

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression

Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity

Contact Info

Product

Resources

About