Title of the paper is “MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia,” published in the February 2013 issue.
Praveen Sethupathy is Co-Senior Author of a paper entititled “MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia,” which is being highlighted by the journal Hepatology in Volume 57, Issue 2, pages 533–542, February 2013.
Abstract:
“Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. Elevated plasma lipid content, or hyperlipidemia, is a significant risk factor for cardiovascular morbidity and mortality. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study we performed high-throughput small RNA sequencing and detected ≈150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its ≈3-fold up-regulation in the liver of mice on a high-fat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (messenger RNA [mRNA] and protein) of several key lipid-metabolism genes, including Angptl3 and Gpam. Finally, we demonstrated that hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis. Conclusion: miR-27b is responsive to lipid levels and controls multiple genes critical to dyslipidemia. (Hepatology 2013)
“Cellular and plasma lipid levels are tightly controlled by complex feed-back and feed-forward mechanisms, which regulate the expression and activity of key metabolic genes at both the transcriptional and posttranscriptional levels. Dysregulation of lipid metabolism can lead to hyperlipidemia, a major risk factor for cardiovascular disease. Several key processes for regulating cellular and systemic lipid levels have been identified; however, posttranscriptional mechanisms remain less well characterized.
“MicroRNAs (miRNAs) are short (≈22 nucleotides) noncoding RNAs that regulate gene expression at the posttranscriptional level. They serve as stable plasma biomarkers for various disorders, are important factors in the pathogenesis of several diseases, and are promising targets of novel therapeutic strategies. In regard to lipid metabolic control, miRNAs have recently been found to modulate cholesterol homeostasis. In vivo inhibition of a liver-specific miRNA, miR-122, significantly lowers plasma cholesterol levels in both mice and nonhuman primates. In addition, miR-33, which is encoded within an intron of SREBF2 and regulates the expression of the ATP-binding cassette transfer protein (ABCA1), a critical player in reverse cholesterol transport and in lipoprotein biogenesis. miR-33 has also been shown to regulate fatty acid oxidation in hepatic cell lines. Nevertheless, despite these important advances, the full extent of posttranscriptional control of lipid metabolism by miRNAs remains incompletely understood and has not been systematically investigated.
“Using an unbiased in silico approach, which should be generally applicable toward the identification of key regulatory miRNAs in any biological process, we predicted miR-27b as a regulatory hub in lipid metabolism. Furthermore, we demonstrated that hepatic miR-27b is responsive to lipid levels and regulates the expression (messenger RNA [mRNA] and protein) of key metabolic genes, including angiopoietin-like 3 (ANGPTL3) and glycerol-3-phosphate acyltransferase 1 (GPAM), which have been implicated previously in the pathobiology of lipid-related disorders.”