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MicroRNA target gene may be linked to NAFLD-related fibrosis

Researchers from the Translational Genomics Research Institute found a potential gene within microRNAs that may be linked to nonalcoholic fatty liver disease-related fibrosis, according to published findings in Translational Research.

“These findings support a role for liver [microRNAs] in the disease development of NAFLD-related damage, and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver damage and eventual liver failure,” Johanna DiStefano, PhD, professor and director of Translational Genomics Research Institute’s (TGen) Diabetes, Cardiovascular & Metabolic Diseases Division, said in a press release.

Johanna DiStefano

DiStefano and colleagues, including Fatjon Leti, research associate at TGen, sequenced microRNAs (miRNAs) from 30 female liver biopsies with evidence of NAFLD, “spelling out their biochemical molecules to identify several potential gene targets associated with NAFLD-related liver damage,” according to the release. Of these biopsies, 15 showed evidence of NAFLD-related fibrosis and 15 did not. For the final analysis, 10 samples negative for NAFLD-related fibrosis were included and compared with the 15 positive fibrosis samples.

Using various technology to extract and sequence the miRNAs, researchers were able to identify several potential genes associated with NAFLD-related liver damage. A total of 75 miRNAs showed significant evidence for differential expression between both groups, including 30 upregulated and 45 downregulated miRNAs (P < .05), according to the research. The 10 most differently expressed miRNAs in the downregulated group were miR-219a, miR-373, miR-378c, miR-590, miR-3611, miR-376b, miR-186, miR-17, miR-1286 and miR-5699. In the upregulated group, the 10 most differentially expressed miRNAs were miR-183, miR-31, miR-150, miR-182, miR-200a, miR-224, miR-92b, miR-3613, miR-708 and miR-766, according to the research.

Fatjon Leti

Of all the miRNAs, miR-182 showed a strong association with FOX03, a protein that has been implicated in hepatic metabolism.

“Because of the known role of miR-182 in mechanisms related to liver cancer, we sought to investigate this miRNA in NAFLD-related liver damage by looking at relevant target genes,” Leti said in the release.

Using the miRanda, miRWalk and miRTarBase algorithms to identify the potential target genes of miR-182, the researchers found FOXO3 and FBXW7.

“We measured levels of both FOXO3 and FBXW7 in F0 and F3–F4 samples … and we observed a significant decrease in both transcript and protein levels of FOXO3 (P = .0001), respectively,” the researchers wrote. “In contrast, we did not find any significant differences in FBXW7 expression … between cases and controls.”

The researchers concluded: “The results obtained in the present study provide evidence of differential levels of a number of hepatic miRNAs in NAFLD-related fibrosis. These data may help to yield new insights into the pathologic mechanisms underlying the development of fibrosis and cirrhosis in NAFLD. Future investigations including validation in independent cohorts and functional characterization of miRNA gene targets and pathways will be important to extend these findings.” – by Melinda Stevens

Disclosures: The researchers report no relevant financial disclosures.