PLoS ONE (Jan 2020)

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

  • Kinya Okamoto,
  • Masahiko Koda,
  • Toshiaki Okamoto,
  • Takumi Onoyama,
  • Kenichi Miyoshi,
  • Manabu Kishina,
  • Tomomitsu Matono,
  • Jun Kato,
  • Shiho Tokunaga,
  • Takaaki Sugihara,
  • Akira Hiramatsu,
  • Hideyuki Hyogo,
  • Hiroshi Tobita,
  • Shuichi Sato,
  • Miwa Kawanaka,
  • Yuichi Hara,
  • Keisuke Hino,
  • Kazuaki Chayama,
  • Yoshikazu Murawaki,
  • Hajime Isomoto

DOI
https://doi.org/10.1371/journal.pone.0219412
Journal volume & issue
Vol. 15, no. 2
p. e0219412

Abstract

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INTRODUCTION:Non-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. METHODS:Eighty 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. One patient was excluded due to low RT-PCR signal. RESULTS:Compared 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, low-density-lipoprotein cholesterol and non-high-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. CONCLUSIONS:Serum 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.