1-fold increase in Δ5-desaturase (Δ5DS) and Fer-1 9.2-fold rise in Δ6-desaturase (Δ6DS) expression. Treatment with UDCA-LPE resulted in a striking down-regulation of both genes to baseline levels with the most pronounced effect on Δ6DS (Fig. 7B). Along this line, fatty acid elongase 5 (ELOVL5), which uses a broad array of C16-22 as substrates, was up-regulated almost six-fold in HFD mice and was decreased to levels of control mice by UDCA-LPE (Fig. 7B). SCD1 expression and protein levels, although not

increased in HFD mice, were reduced accordingly after UDCA-LPE administration (Fig. 7B, Supporting Fig. 4). Finally, analysis of diacylglycerol acyltransferase (DGAT) 1 and 2 revealed a drop in DGAT1 expression upon the HFD, which was reversed significantly by UDCA-LPE. Expression of DGAT2 showed a similar tendency with a slight decrease in learn more HFD mice and a moderate increase upon UDCA-LPE administration, but without reaching significance (Fig. 7C). Because currently available therapeutic approaches to NAFLD show rather limited effectiveness, novel treatment strategies are needed. We report here that UDCA-LPE, a synthetic bile acid–phospholipid conjugate, exerted potent hepatoprotective functions in two different dietary mouse models of NAFLD. Improvement in HFD and MCD diet-induced elevation of aminotransferases was further accompanied by considerable reduction in hepatic lipid overloading.

Moreover, the conjugate showed distinct anti-inflammatory properties, with the ability to down-regulate essential proinflammatory genes and to reduce levels of cytotoxic lipid intermediates such as LPC. Administration of UDCA-LPE further resulted in an inhibition of up-regulated genes crucial to de novo lipogenesis and fatty acid desaturation. Thus, UDCA-LPE has highly favorable characteristics for the treatment of

NAFLD. Proinflammatory cytokines and chemokines are crucial factors in the pathogenesis of NAFLD, perpetuating apoptosis and inflammation during disease progression. Chemokines like MCP1 were found to be up-regulated in the early phase of murine NAFLD23 and were also reported to be elevated in the plasma of NAFLD patients, exhibiting an association with disease severity24 Moreover, MCP1 was capable of inducing steatosis in cultured hepatocytes,25 Dimethyl sulfoxide and murine knockout of its receptor CCR2 as well as pharmacological antagonism of CCR2 efficiently lowered hepatic steatosis in mice fed an HFD, even indicating a direct role for MCP1 during lipogenesis26 Gut-derived endotoxins such as LPS have been implicated in the triggering of Kupffer cell activation with subsequent liberation of cytokines like TNF-α,13, 14 known to be critically involved in hepatocellular apoptosis. Recent data further revealed that steatotic primary hepatocytes derived from NAFLD livers are more sensitive to TNF-α–mediated apoptotic cell death than nonsteatotic control cells.