Abstract
Recent studies have indicated that the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway is closely involved in liver fibrosis and other fibrotic diseases. However, whether targeting the AMPK pathway can rescue liver fibrosis and its complications, such as portal hypertension, is unknown. This study aimed to explore the therapeutic value of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside), an agonist of the AMPK pathway, on liver fibrosis and portal hypertension in bile duct ligation (BDL) rats. In vitro experiments showed that the gene expression levels of TGF-b, a-SMA, and collagen 1 in primary rat hepatic stellate cells (HSCs) were significantly decreased after AICAR treatment. The p-eNOS expression and nitric oxide (NO) production were increased by AICAR administration in sinusoidal endothelial cells (SECs). For in vivo animal studies, AICAR acutely decreased portal pressure in the BDL and CCL4 fibrotic rats, but not in the partial portal vein ligation (PVL) rats, without changes in systemic hemodynamics. It was also observed by using intravital fluorescence microscopy that AICAR led to sinusoidal vasodilation in situ experiment. We propose that the relevant mechanisms may be related to the activation of the AMPK/NO pathway in SECs and that this activation promoted NO production in the liver, thereby promoting hepatic sinusoid microcirculation and decreased intrahepatic resistance. The results were verified using the NO inhibitor L-NAME. Chronic AICAR treatment also showed profound beneficial effects on the BDL model rats. The hemodynamic condition was greatly improved, but the positive effect could be partially blocked by L-NAME. Moreover, AICAR also decreased hepatic fibrogenesis in the BDL rats.Key messagesAcute and chronic use of AICAR could alleviate portal pressure without changing systemic hemodynamics.AICAR induced sinusoidal vasodilation by improving NO bioavailability and ameliorating endothelial dysfunction in vivo and in vitro.AICAR could alleviate liver cirrhosis in the BDL model rats.
Highlights
Liver fibrosis is one of the leading causes of mortality worldwide regardless of recent therapeutic advances [1]
The TGF-β and α-SMA mRNA levels decreased to 56.4% and 64.6%, respectively, when the hepatic stellate cells (HSCs) were treated with 1 mmol/L AICAR. mRNA levels were further decreased to 32.8% and 47.7%, respectively, after the cells were treated with 5 mmol/L AICAR (Supplementary Fig. 1A and 1B)
COL-1 decreased to 47.1% after 5 mmol/L AICAR treatment (Supplementary Fig. 1E)
Summary
Liver fibrosis is one of the leading causes of mortality worldwide regardless of recent therapeutic advances [1]. It is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. In addition to deposition of extracellular matrix components, the pathogenesis of liver fibrosis is associated with vascular remodeling. Portal hypertension (PHT) is one of the major complications of liver cirrhosis and is characterized by increased hepatic portal vein pressure gradient (HPVG) [2]. Upper gastrointestinal bleeding and hepatic failure caused by severe PHT still have high mortality rates in clinical settings [2, 3]. The pathophysiological process of PHT is complicated.
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