CB1 Antisense in the Treatment of Liver Fibrosis

• Main Authors: Pei-xuan Su, 蘇佩萱
• Other Authors: Chang-Chun Hsiao
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/5er46b

碩士 === 國立中山大學 === 生物醫學研究所 === 102 === Liver fibrosis results from chronic injury to the liver and inflammation activation of hepatic stellate cells produce excessive accumulation of type I collagen proteins, ultimately leads to cirrhosis, a major public health in Taiwan. Cannabinoid receptor 1 (CB1) was highly induced in human cirrhotic samples. CB1 transgenic mice (CB1 overexpression) induced by carbon tetrachloride (CCl4 ) for 4 weeks with higher liver fibrosis level than the wild type mice. Collagen type I in liver tissue of CB1 transgenic mice is higher than wild type mice by Masson’s trichrome stain and immunohistochemistry(IHC) stain. Both CB1 and α-SMA Immunohistochemistry (liver fibrosis biomarker) expression in liver tissue of CB1 transgenic mice significantly increased compared with the wild type mice. Overexpression of CB1 promotes progression of fibrosis. This suggests that CB1 antisense oligonucleotide may have therapeutics effect for liver fibrosis. B6 mice with CCl4-induced liver fibrosis were randomized to receive CB1 antisense oligonucleotide, CB1 sense oligonucleotide, or the CB1 antagonist AM251 for 4 weeks. After B6 mice with liver fibrosis had 28 days CB1 antisense oligonucleotide treatment, type I collagen expression in liver tissue of CB1 antisense oligonucleotide therapy group returned to similar with normal mice. The CB1, α-SMA expression in liver tissue of CB1 antisense oligonucleotide therapy group were also significantly decreased compared with the liver fibrosis mice. The hepatic IL-6 expression in CB1 antisense oligonucleotide therapy group was significantly decreased than liver fibrosis group. For serum albumin expression respect, CB1 antisense oligonucleotide therapy group were higher than both liver fibrosis mice and normal mice. The CB1 antisense oligonucleotide therapy group liver function is restored to normal. Genetic and pharmacologic blockade of CB1 by CB1 antisense oligonucleotide and AM251 attenuated liver fibrosis level and can repair liver fibrosis mice hepatic function to normal. Modulation of CB1 signaling has therapeutic potential for liver fibrosis.