circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis

Abstract

Hepatic steatosis reflects the miRNA-related pathological disorder with triglyceride accumulation and lipid peroxidation, which leads to nonalcoholic steatohepatitis, liver fibrosis/cirrhosis, and even hepatocellular carcinoma. Circular RNA (circRNA)/miRNA interaction reveals a novel layer of epigenetic regulation, yet the miRNA-targeting circRNA remains uncertain in hepatic steatosis. Here, we uncover circRNA_0046367 to be endogenous modulator of miR-34a that underlies hepatic steatosis. In contrast to its expression loss during the hepatocellular steatosis in vivo and in vitro, circRNA_0046367 normalization abolished miR-34a's inhibitory effect on peroxisome proliferator-activated receptor α (PPARα) via blocking the miRNA/mRNA interaction with miRNA response elements (MREs). PPARα restoration led to the transcriptional activation of genes associated with lipid metabolism, including carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA binding domain containing 3 (ACBD3), and then resulted in the steatosis resolution. Hepatotoxicity of steatosis-related lipid peroxidation, being characterized by mitochondrial dysfunction, growth arrest, and apoptosis, is resultantly prevented after the circRNA_0046367 administration. These findings indicate a circRNA_0046367/miR-34a/PPARα regulatory system underlying hepatic steatosis. Normalized expression of circRNA_0046367 may ameliorate the lipoxidative stress on the basis of steatosis attenuation. circRNA_0046367, therefore, is suggested to be potential approach to the therapy of lipid peroxidative damage.

Antagonizing circRNA_002581–miR-122–CPEB1 axis alleviates NASH through restoring PTEN–AMPK–mTOR pathway regulated autophagy

“…4, 5). Although several recent studies have reported that circRNAs play an important role in the stage of simple steatosis 9,32,33 , it is the first time the current study demonstrates that circRNA participates in the progression of NASH and circRNA_002581 may serve as a novel therapeutic target for the treatment of NASH.…”

“…For instance, circRNA Cdr1as was reported to regulate insulin transcription and secretion in islet cells via binding to miR-7 and further influence its downstream target mRNAs expression 7 . Nevertheless, current reports on the circRNA in NAFLD have been rarely reported, including the metformininduced changes of the coding transcriptome and noncoding RNAs in NAFLD mice 8 and the prevention of hepatocyte lipid peroxidation and steatosis by cir-cRNA_0046367 9 . Therefore, circRNA function in NAFLD is a novel research arena and calls for further intensive study.…”

Hsa_circ_101280 promotes hepatocellular carcinoma by regulating miR‐375/JAK2

“…Circ‐S‐7 was demonstrated to participate in gastric cancer by interacting with miR‐7 . In hepatic steatosis cells, restoration of hsa_circ_0046367 reduced miR‐34a‐induced PPARα inhibition . In addition, several studies have examined the circRNA‐miRNA‐mRNA axis in HCC cells.…”

“…39 In hepatic steatosis cells, restoration of hsa_circ_0046367 reduced miR-34a-induced PPARa inhibition. 40 In addition, several studies have examined the circRNA-miRNA-mRNA axis in HCC cells. Fu et al revealed that hsa_circ_0005986 directly interacted with miR129-5p, thereby regulating the mRNA expression level of Notch1.…”

The circFASN/miR-33a pathway participates in tacrolimus-induced dysregulation of hepatic triglyceride homeostasis

“…23 Guo et al found that circFASN expression is lost during hepatic steatosis, suggesting a circFASN-dependent regulatory system in lipid metabolism. 40 Bioinformatically, miR-33a was recognized as a target of circFASN based on circBase (http://www.circbase.org/) and miRBase (http:// microrna.sanger.ac.uk/) analyses. [41][42][43] Experimentally, dual-luciferase reporter assays provided further verification that circFASN acts as a miR-33a "sponge".…”