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

Abstract EN

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.