miR1908-5p regulates energy homeostasis in hepatocyte models.
Sci Rep
; 11(1): 23748, 2021 12 09.
Article
em En
| MEDLINE
| ID: mdl-34887471
ABSTRACT
We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and then showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c. The link to LDL-C was subsequently validated and clarified by the identification of a miR1908-5p-TGFB-LDLR regulatory axis. Here, we continue our investigations on miR1908-5p function by leveraging human primary hepatocytes and HuH-7 hepatoma models. Expression of miR1908-5p was shown to be sensitive to glucose and agents affecting glucose metabolism. Transcriptome-wide changes in primary hepatocytes and HuH-7 cells treated with a miR1908-5p mimic were investigated by enrichment approaches to identify targeted transcripts and cognate pathways. Significant pathways included autophagy and increased mitochondrial function. Reduced activation and/or levels of several key energy and metabolic regulators (AKT, mTOR, ME1, G6PD, AMPK and LKB) were subsequently confirmed in mimic treated HuH-7 cells. These effects were associated with reduced NADPH to NADP+ ratio in HuH-7 cells. LKB1 was validated as a direct target of miR1908-5p, the reintroduction of which was however insufficient to compensate for the impact of the miR1908-5p mimic on AMPK and ACC1. These findings implicate miR1908-5p in metabolic and energy regulation in hepatocyte models via multiple, independent, pathways.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Hepatócitos
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MicroRNAs
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Interferência de RNA
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Metabolismo Energético
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article