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.
Highlights
We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c
In primary hepatocytes and hepatocarcinoma cell lines, we show that miR1908-5p is linked to several processes, including suppression of two antagonistic pathways and a reduction in NADPH/ NADP+ levels in HuH-7 cells
We identify Liver Kinase B1 (LKB1) as a miR1908-5p target in both HuH-7 cells and primary hepatocytes. These findings demonstrate a role for miR1908-5p in the regulation of hepatocyte energy metabolism via the reprogramming of antagonistic pathways
Summary
We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c. 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. LKB1 was validated as a direct target of miR1908-5p, the reintroduction of which was 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. AKT is implicated in the AKT/Mammalian target of rapamycin (mTOR) cascade which promotes growth and/or proliferation[7] The latter axis suppresses the Liver Kinase B1 (LKB1)- 5′AMP-activated protein kinase (AMPK) axis, whose role is to redress low energy states by increasing catabolism and reducing a nabolism[8,9,10]. These findings demonstrate a role for miR1908-5p in the regulation of hepatocyte energy metabolism via the reprogramming of antagonistic pathways
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
