The Dark That Matters: Long Non-coding RNAs as Master Regulators of Cellular Metabolism in Non-communicable Diseases

Abstract

Non-coding RNAs are pivotal for many cellular functions, such as splicing, gene regulation, chromosome structure, and hormone-like activity. Here, we will report about the biology and the general molecular mechanisms associated with long non-coding RNAs (lncRNAs), a class of >200 nucleotides-long ribonucleic acid sequences, and their role in chronic non-transmissible diseases. In particular, we will summarize knowledge about some of the best-characterized lncRNAs, such as H19 and MALAT1, and how they regulate carbohydrate and lipid metabolism as well as protein synthesis and degradation. Evidence is discussed about how lncRNAs expression might affect cellular and organismal metabolism and whether their modulation could provide ground for the development of innovative treatments.

Keywords: amino acids; cancer; carbohydrates; cardiovascular; diabetes; lipids; lncRNA; metabolism.

FIGURE 1

Carbohydrate and protein metabolisms. Red: lncRNAs; green: proteins; blue: transcriptor factors; brown: nuclear receptors. PPARγ promoter binds directly Ftx increasing the transcription. PPARγ is phosphorylated through AMPK pathway and it enhances the transcription of leptin, tumor necrosis factor α (TNFα), glucose channel 4 (GLUT4) and pyruvate dehydrogenase kinase 1 (PDK1). In turn, AMPK activity is enhanced by the binding to NBR2. H19 influences the transcription of pyruvate kinase M2 probably by the inhibition of PKM2 miRNAs, however, more studies are necessary to elucidate the molecular mechanism. The glucocorticoid receptor (GR) is blocked by Gas5 which interacts to GR DNA binding domain resulting in an inhibition of 6-phosphoglucanase (G6Pase) and phosphoenolpyruvate carboxykinase (PFKFB2). LINC00092 stabilizes phosphofructo-2-kinase/fructose-2,6-phosphatase 2 (PFKFB2) mRNA allowing its synthesis. LINC00116 encodes the microprotein mitoregulin (Mtln) which acts into mitochondrial inner membrane increasing the formation of supercomplexes, calcium intake and reducing ROS formation. The alteration of LINC00116 generate dysfunctional of low levels of Mtln. As-SLC7A11 binds SLC7A11 mRNA inhibiting the translation of cysteine/glutamine transporter, meanwhile plasmacytoma variant translocation 1 (PVT1) enhance the synthesis of AA transporter through the binding of miR-126 which is a suppressor of SCL7A5 mRNA.

FIGURE 2

Lipid metabolism. Red: lncRNA; green: proteins; blue: transcriptional factors; gray: miRNAs. Sterol regulatory element binding protein 1c (SREBP1c) can be modulated in different ways: directly binding MALAT1 or by poly-pyrimidine tract-binding protein 1 (PTBP1) that, in turn, binds H19. As result genes involved in lipid anabolism are expressed. The long non-coding RNA lncLSTR inhibits TAR DNA-binding protein 43 (TDP-43) blocking the transcription of sterol 12 α hydroxylase and increasing the hyperlipidemia. Moreover, the hyperlipidemia is enhanced by the inhibition of APO synthesis through the chromatin condensation at APO promoters by the hypomethylation condition of histone 3 at lysine 4 and 27 due to APOA1-As bound. In addition, farnesoid X receptor (LXR) and APOA4 mRNAs are inhibited by lncLSTR and HuR protein helped by APOA4-As respectively reducing the clearance of plasmatic fatty acids. In hypercholesteremia a positive feedback has been shown in which HULC enhances PPARα synthesis. One effect is the increasing of retinoic acid X-receptor alpha (RXRA) level which recognizes and positively regulates HULC promoter.