Uraki Satoko, Tameda Masahiko, Sugimoto Kazushi, Shiraki Katsuya, Takei Yoshiyuki, Nobori Tsutomu, Ito Masaaki
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan; Department of Molecular and Laboratory Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan; Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan.
PLoS One. 2015 Jun 29;10(6):e0131346. doi: 10.1371/journal.pone.0131346. eCollection 2015.
BACKGROUND & AIMS: It has been suggested that amino acid (aa) substitution at position 70 from arginine (70R) to glutamine (70Q) in the genotype 1b hepatitis C virus (HCV) core protein is associated with insulin resistance and worse prognosis. However, the precise mechanism is still unclear. The aim of this study was to investigate the impact of the substitution at position 70 in HCV core protein on adipokine production by murine and human adipocytes.
The influence of treatment with HCV core protein (70R or 70Q) on adipokine production by both 3T3-L1 and human adipocytes were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and triglyceride content was also analyzed. The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined.
IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%.
Our study suggests that extracellular HCV core protein with substitution at position 70 enhanced IL-6 production and reduced adiponectin production from visceral adipose tissue, which can cause insulin resistance, hepatic steatosis, and ultimately development of HCC.
有研究表明，1b型丙型肝炎病毒（HCV）核心蛋白第70位氨基酸由精氨酸（70R）替换为谷氨酰胺（70Q）与胰岛素抵抗及更差的预后相关。然而，确切机制仍不清楚。本研究旨在探讨HCV核心蛋白第70位氨基酸替换对小鼠和人脂肪细胞脂肪因子产生的影响。
采用实时定量PCR和酶联免疫吸附测定（ELISA）检测HCV核心蛋白（70R或70Q）处理对3T3-L1细胞和人脂肪细胞脂肪因子产生的影响，并分析甘油三酯含量。检测Toll样受体（TLR）2/4抑制对HCV核心蛋白诱导的3T3-L1细胞白细胞介素-6（IL-6）产生的影响。
与70R核心蛋白相比，用70Q处理小鼠和人脂肪细胞后，IL-6产生显著增加，脂联素产生减少，甘油三酯含量无变化。用抗TLR2抗体可使70Q HCV核心蛋白处理的3T3-L1细胞IL-6诱导显著抑制42%，用TLR4抑制剂可抑制40%。
我们的研究表明，第70位氨基酸有替换的细胞外HCV核心蛋白可增强内脏脂肪组织IL-6产生并减少脂联素产生，这可导致胰岛素抵抗、肝脂肪变性，并最终引发肝癌。
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