Journal Article

Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis

Oh, Jae-Won, Sugito, Nobuhiko, Kawaguchi, Nao, Takai, Shinji, Uchiyama, Kazuhisa, Lee, Sang-Woong, Kim, Kwang-Pyo, Inomata, Yosuke, Taniguchi, Kohei, Hirokawa, Fumitoshi, Akao, Yukihiro

2022

Overview

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Binding sites / Cancer / Disease Models, Animal / Down-Regulation / Fatty liver / Gene expression / Glycolysis / Histopathology / Inflammation / Kinases / Kupffer Cells - metabolism / Lipids / Liver / Liver cancer / Liver cirrhosis / Liver Neoplasms - metabolism / Localization / Metabolism / Mice / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Muscles - metabolism / Non-alcoholic Fatty Liver Disease - metabolism / Pathophysiology / Phosphorylation / Protein expression / Proteins / Pyruvate Kinase - genetics / Pyruvate Kinase - metabolism / Rats / Rodents