Abstract
BACKGROUND and Aims: We and others have previously shown, that the hepatic endocannabinoid (EC) system becomes activated and plays an important role in liver fibrogenesis. However, cellular origin and mechanisms that lead to increased EC levels (e.g. 2-arachydonoyl glycerol, 2-AG) are unknown. We analysed expression of the major 2-AG-generating enzyme diacylglycerol lipase (DAGL)-beta and the main degrading enzyme monoacylglycerol-lipase (MGL) in different hepatic cell populations as well as in normal and fibrotic mouse livers at different timepoints after bile duct ligation (BDL). Methods: Primary mouse hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) were isolated by collagenase perfusion or MACS, respectively. 2-AG was measured by LC/MS in mouse livers 2, 7 and 14 days after BDL or sham operation (n=6 each). Alpha-SMA, DAGL-beta, FAAH and MGL mRNA and protein expression were determined by qRT PCR and Westernblot. Results: Hepatic 2-AG levels were increasingly elevated >2.5-fold 14 days (p< 0.05) after BDL. Interestingly, mRNA and protein expression of the 2-AG production enzyme DAGL beta was highest in LSECs, second highest in HSCs and third highest in KCs, the degradation enzyme MGL was highest in LSECs and HSCs, respectively. Hepatocytes did not express notable levels of either enzyme. During the timecourse of fibrogenesis, mRNA and protein expression of DAGL-beta in whole liver tissue was significantly increased, whereas MGL expression decreased significantly, thus correlating with increasing 2-AG levels and alpha-SMA expression. Conclusion: In the liver, 2-AG is mainly produced and degraded by LSECs and HSCs. Elevated 2-AG levels during fibrogenesis result from increased production and decreased degradation. The data further points to LSECs or HSCs rather than hepatocytes or KCs being the most important hepatic cell populations in 2-AG metabolism in fibrogenesis.
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