Department of Clinical Pharmacology and Visceral Research, University of Bern, Switzerland.
Mol Med. 2011;17(11-12):1285-94. doi: 10.2119/molmed.2011.00149. Epub 2011 Aug 19.
The cannabinoid system (CS) is implicated in the regulation of hepatic fibrosis, steatosis and inflammation, with cannabinoid receptors 1 and 2 (CB1 and CB2) being involved in regulation of pro- and antifibrogenic effects. Daily cannabis smoking is an independent risk factor for the progression of fibrosis in chronic hepatitis C and a mediator of experimental alcoholic steatosis. However, the role and function of CS in alcoholic liver fibrosis (ALF) is unknown so far. Thus, human liver samples from patients with alcoholic liver disease (ALD) were collected for analysis of CB1 expression. In vitro, hepatic stellate cells (HSC) underwent treatment with acetaldehyde, Δ9-tetrahydrocannabinol H₂O₂, endo- and exocannabinoids (2-arachidonoylglycerol (2-AG) and [THC]), and CB1 antagonist SR141716 (rimonabant). In vivo, CB1 knockout (KO) mice received thioacetamide (TAA)/ethanol (EtOH) to induce fibrosis. As a result, in human ALD, CB1 expression was restricted to areas with advanced fibrosis only. In vitro, acetaldehyde, H₂O₂, as well as 2-AG and THC, alone or in combination with acetaldehyde, induced CB1 mRNA expression, whereas CB1 blockage with SR141716 dose-dependently inhibited HSC proliferation and downregulated mRNA expression of fibrosis-mediated genes PCα1(I), TIMP-1 and MMP-13. This was paralleled by marked cytotoxicity of SR141716 at high doses (5-10 μmol/L). In vivo, CB1 knockout mice showed marked resistance to alcoholic liver fibrosis. In conclusion, CB1 expression is upregulated in human ALF, which is at least in part triggered by acetaldehyde (AA) and oxidative stress. Inhibition of CB1 by SR141716, or via genetic knock-out protects against alcoholic-induced fibrosis in vitro and in vivo.
大麻素系统（CS）参与肝纤维化、脂肪变性和炎症的调节，大麻素受体 1 和 2（CB1 和 CB2）参与调节促纤维化和抗纤维化作用。每天吸食大麻是慢性丙型肝炎纤维化进展的独立危险因素，也是实验性酒精性脂肪变性的中介。然而，到目前为止，CS 在酒精性肝纤维化（ALF）中的作用和功能尚不清楚。因此，收集了酒精性肝病（ALD）患者的人肝组织样本进行 CB1 表达分析。在体外，肝星状细胞（HSC）用乙醛、Δ9-四氢大麻酚 H₂O₂、内源性和外源性大麻素（2-花生四烯酸甘油（2-AG）和[THC]）以及 CB1 拮抗剂 SR141716（利莫那班）进行处理。在体内，CB1 敲除（KO）小鼠接受硫代乙酰胺（TAA）/乙醇（EtOH）诱导纤维化。结果，在人类 ALD 中，CB1 表达仅局限于纤维化进展的区域。在体外，乙醛、H₂O₂以及 2-AG 和 THC，单独或与乙醛联合，诱导 CB1 mRNA 表达，而 CB1 阻断剂 SR141716 以剂量依赖性方式抑制 HSC 增殖并下调纤维化介导基因 PCα1（I）、TIMP-1 和 MMP-13 的 mRNA 表达。这与高剂量（5-10 μmol/L）SR141716 的显著细胞毒性平行。在体内，CB1 敲除小鼠对酒精性肝纤维化表现出明显的抵抗力。总之，CB1 在人类 ALF 中表达上调，至少部分是由乙醛（AA）和氧化应激引起的。SR141716 通过抑制 CB1 或通过基因敲除，在体外和体内均可预防酒精引起的纤维化。
