Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease

Okamoto, K.; Koda, M.; Okamoto, T.; Onoyama, T.; Miyoshi, K.; Kishina, M.; Matono, T.; Kato, J.; Tokunaga, S.; Sugihara, T.; Hiramatsu, A.; Hyogo, H.; Tobita, H.; Sato, S.; Kawanaka, M.; Hara, Y.; Hino, K.; Chayama, K.; Murawaki, Y.; Isomoto, H.

doi:10.1101/688903

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bioRxiv · 10.1101/688903

Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease

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Abstract

IntroductionNon-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.\n\nMethodsEighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control.\n\nResultsCompared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, and low-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.\n\nConclusionsSerum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

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Okamoto, K., Koda, M., Okamoto, T., Onoyama, T., Miyoshi, K., Kishina, M., Matono, T., Kato, J., Tokunaga, S., Sugihara, T., Hiramatsu, A., Hyogo, H., Tobita, H., Sato, S., Kawanaka, M., Hara, Y., Hino, K., Chayama, K., Murawaki, Y., Isomoto, H.. 2019-07-01. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. https://doi.org/10.1101/688903

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