miR1908-5p regulates energy homeostasis in hepatocyte models

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.

miR-1908 Dysregulation in Human Cancers

“…The current study shows that miR-1908 is involved in the regulation of the MAPK signaling pathway ( 6 ), TGF-β signaling pathway ( 1 , 7 ), PI3K/AKT signaling pathway ( 8 , 9 ), and AMPK signaling pathway ( 10 ).…”

“…LKB1 is an important upstream kinase of the AMPK signaling pathway that controls cell metabolism and growth in tumor suppression ( 72 ). In liver cancer cell HuH-7, miR-1908-5p could downregulate the expression of LKB1 and further inhibit the activity of AMPK ( 10 ). This may be related to the occurrence of obesity, but the mechanism of miR-1908-5p in the process of hepatocarcinogenesis is still not fully understood.…”

“…miR-1908 is abnormally expressed in various diseases, especially cancer. Studies have shown that miR-1908 can target at least 27 genes and is involved in multiple cancer-related signaling pathways, including regulation of the MAPK signaling pathway ( 6 ), TGF-β signaling pathway ( 1 , 7 ), PI3K/AKT signaling pathway ( 8 , 9 ), and AMPK signaling pathway ( 10 ). miR-1908 regulates cell behaviors such as cell proliferation, differentiation, apoptosis, invasion and metastasis, and exosome secretion by regulating downstream genes, and plays an important role in the occurrence and development of various diseases such as cancer.…”

Ferroptosis Altered microRNAs Expression in HT-1080 Fibrosarcoma Cells Based on Small RNA Sequencing and Bioinformatics Analysis

“…miR-1908-5p was the down-regulated DE-miRNA with the highest fold change. A previous study has reported that miR-1908-5p was involved in metabolic and energy regulation through multiple independent pathways in hepatocytes [ 30 ]. miR-128-1-5p expression was reduced in mice following myocardial ischemia/reperfusion injury and negatively regulated its direct target Gadd45g, leading to cardiomyocyte apoptosis [ 31 ].…”