Epigenetic Regulation Associated With Sirtuin 1 in Complications of Diabetes Mellitus

Abstract

Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD⁺)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.

Keywords: SIRT1; deacetylation; diabetes mellitus; diabetic complications; epigenetics.

Figure 1

The mechanisms of action and signaling pathways of SIRT1 in diabetic cardiomyopathy. Diabetes mellitus (DM) can inhibit SIRT1 expression by increased expression of PARP1, miR-34a, and miR-195, or by decreased expression of miR-22. SIRT1 can deacetylate NF-κB and H3K9 to inhibit the expression of NF-κB-dependent inflammatory genes, which improves DCM. Dysregulation of Dnmt3b and SIRT1 by DM leads to CpG demethylation and histone H3 acetylation at the p66Shc promoter, which can result in sustained transcription of p66Shc to cause cardiac oxidative stress and inflammation. SIRT1 can reduce Drp1-mediated mitochondrial fission to exert its cardioprotective role in DCM through increasing PGC-1α expression. 1,25(OH)₂D₃ treatment can inhibit PARP1 expression to increase the expression of SIRT1 and repress the phosphorylation of mTOR, thus improving DM-induced cardiac hypertrophy and fibrosis. And SIRT1 can deacetylate FOXO1 and enhance FOXO1 DNA binding at the Rab7 promoter region to ameliorate dysfunctional autophagic flux in the hearts of diabetic mice. Finally, lncRNA HOTAIR can upregulate SIRT1 expression by sponging miR-34a to improve DCM. SIRT1, Sirtuin 1; DM, diabetes mellitus; PARP1, poly (ADP-ribose) polymerase 1; miR, microRNA; NF-κB, nuclear factor kappa B; Dnmt3b, DNA methyltransferase 3b; DCM, diabetic cardiomyopathy; Drp1, dynamin-related protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha 1,25(OH)₂D_3, 1,25-Dihydroxyvitamin D3; mTOR, mammalian target of rapamycin; FOXO1, forkhead box O 1; lncRNA HOTAIR, long non-coding RNA HOX transcript antisense RNA.

Figure 2

The mechanisms of action and signaling pathways of SIRT1 in diabetic nephropathy. Diabetes mellitus (DM) can inhibit SIRT1 expression by increased expression of miR-34a-5p, miR-221, miR-9, miR-133b, miR-155-5p, and miR-199b. HIC1 can repress SIRT1 transcription in response to HG stimulation via an interaction with EZH2 and Dnmt1. Overexpression of SIRT1 can blunt CLDN1/β-catenin-Snail-mediated albuminuria in DN via the deacetylation of histones H3 and H4 with subsequent CpG methylation of Cldn1 by recruiting Dnmt1. SIRT1 activation can inhibit p66Shc expression to improve oxidative stress in DN by deacetylation of acetyl-H3. SIRT1 activation can upregulate miR-29 expression by reduction of NF-κB binding to its promotor. Overexpression of miR-29 directly targets Keap1 mRNA to decrease Keap1 expression and subsequently increase Nrf2 expression. Free Nrf2 translocates to the nucleus, where it dimerizes with members of the sMaf family and binds to ARE within regulatory regions of a wide variety of cell defense genes, including GST and NQO1. LincRNA 1700020I14Rik can interact with miR-34a-5p to inhibit cell proliferation and fibrosis in DN though the SIRT1/HIF-1α signaling pathway. LncRNA GAS5 and SOX2OT can upregulate SIRT1 expression by sponging miR-221 and miR-9, respectively. SIRT1 can inhibit TGF-β1-induced renal fibrosis and NOX4-induced oxidative stress, and stimulate PGC-1α-mediated mitochondrial biogenesis to improve DN. Finally, SIRT1 can deacetylate and activate FOXO1 to upregulate the level of autophagy, and deacetylate and inhibit p53 to inhibit apoptosis, thus improving DN. SIRT1, Sirtuin 1; DM, diabetes mellitus; miR, microRNA; HIC1, hypermethylated in cancer 1; HG, high glucose; EZH2, enhancer of zeste homolog 2; Dnmt1, DNA methyltransferase 1; CLDN1, claudin-1; DN, diabetic nephropathy; NF-κB, nuclear factor kappa B; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; sMaf, small Maf; ARE, antioxidant response element; GST, glutathione S-transferase; NQO1, nicotinamide adenine dinucleotide phosphate (NADPH) quinone dehydrogenase 1; LincRNA, long intergenic non-coding RNA; HIF-1α, hypoxia-inducible factor-1α; LncRNA GAS5, long non-coding RNA growth arrest special 5; SOX2OT, SOX2-overlapping transcript; TGF-β1, transforming growth factor-beta 1; NOX4, NADPH oxidase 4; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha FOXO1, forkhead box O 1; p53, tumor protein 53.