12 Accordingly, in our current study we confirmed that UDCA-LPE w

12 Accordingly, in our current study we confirmed that UDCA-LPE was able to dampen the susceptibility of the liver toward extrinsic apoptosis as well as the inflammatory response, with a

pronounced down-regulation of mediators such as MCP1, VCAM1, or TNF-α, which are responsible for leukocyte recruitment to the site of inflammation. MCP1 has also been described to be involved in the process of selleck inhibitor chemotaxis and fibrogenic activation of stellate cells,28, 29 leading to TGF-β1 and extracellular matrix production. Currently, our preliminary observations indicate that UDCA-LPE may be capable of impairing fibrotic response due to the MCD diet (unpublished data). Thus, based on ongoing experimental studies, potentially beneficial effects of UDCA-LPE on hepatofibrogenesis should be addressed in the Saracatinib order future. Lipotoxicity attributable to potent proinflammatory lipid intermediates has been implicated in deteriorating parenchymal damage during NAFLD. The phospholipase A2 (PLA2) cleavage product LPC, which plays a pivotal role in different inflammatory conditions,30-32 mediates hepatocellular apoptosis due

to palmitate-induced lipotoxicity.33 Furthermore, LPC levels were found to be elevated in livers of NAFLD patients.4 Earlier studies showed that LPC abundance in mitochondria is able to induce hepatocellular death34 caused by mitochondrial membrane depolarization.35 Our results proved that UDCA-LPE is capable of lowering increased LPC pools in dietary NAFLD, as previously demonstrated for acute liver injury in vitro and in vivo.12 Additionally, HFD mice treated with UDCA-LPE displayed reduced serum activity of PLA2 (unpublished observations), which

Dipeptidyl peptidase was previously reported to be necessary for lipid droplet biogenesis.36 Thus, inhibition of PLA2 may serve as a further mechanism for how the conjugate prevents hepatic lipid accumulation by way of inflammation inhibition. Further experimental studies are needed to prove this hypothesis. Excessive hepatic fat deposits may further serve as a prerequisite for subsequent liver injury due to lipid peroxidation. Enhanced ROS formation in NASH may oxidize unsaturated lipids to generate lipid peroxidation products.37 In our study, treatment with UDCA-LPE achieved a marked reduction in lipid hydroperoxides in mice fed an MCD diet, which has been previously shown to cause extensive increase in these cytotoxic lipid byproducts.38 Hepatic fat accumulation accompanied by changes in lipid metabolism is an essential pathophysiological feature of NAFLD. In accordance with earlier studies in humans,39, 40 HFD mice displayed up-regulation of de novo lipogenesis with enhanced expression of FASN and ACC1 as well as a moderate increase in SREBP1c, which is largely responsible for the regulation of enzymes involved in fatty acid synthesis.

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