Beneficial Effects of SREBP Decoy Oligodeoxynucleotide in an Animal Model of Hyperlipidemia

Abstract

Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.

Decoy Technology as a Promising Therapeutic Tool for Atherosclerosis

“…Another important issue related to decoy technology is the delivery strategy, which determines the in vivo efficacy and/or specificity. [85]…”

“…SREBP controls homeostasis of lipids by regulating the expression of enzymes required for the synthesis of fatty acids, triacylglycerol, endogenous cholesterol, and phospholipids [ 85 ]. An et al used the SREBP decoy ODN to inhibit SREBPs in high-fat diet fed hyperlipidemic mice.…”

“…Results showed that the decoy could inhibit the increased expression of fatty acid synthetic pathways, including SREBP-1c, ACC1, SCD-1, FAS, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR). Moreover, decoy treatment decreased pro-inflammatory cytokines, such as interleukin (IL)-8, IL-1β, TNF-α, and IL-6 expression [ 85 ].…”

Based on Network Pharmacology and RNA Sequencing Techniques to Explore the Molecular Mechanism of Huatan Jiangzhuo Decoction for Treating Hyperlipidemia

“…It transcriptionally regulates the expression of its downstream lipogenic genes involving in the synthesis of fatty acid and triglyceride [ 36 , 37 ]. It is noted that the activation of AMPK could inhibit the activation of Srebp1 and acetyl-CoA carboxylase 1 (Acc1), leading to the reduction of lipid biosynthesis [ 38 ].…”

Application of decoy oligodeoxynucleotides strategy for inhibition of cell growth and reduction of metastatic properties in nonresistant and erlotinib‐resistant SW480 cell line

“…Considering the benefits of TFD over the other STAT3 inhibitor strategies, such as small interfering RNA and monoclonal antibodies, specificity and efficiency in target binding, alongside the lower expenses of decoy ODNs synthesis, provides interest to the researchers (An et al, 2020; Gwon et al, 2020). Despite limitations in clinical development of ODNs in terms of stability and effective cell transfer, structural modifications are proposed to overcome these barriers and introduce ODNs as therapeutic candidates, especially in cases of drug resistance (Hecker & Wagner, 2017; Rao et al, 2020).…”