41 We were able to establish that treatment with UDCA-LPE achieved a clear reduction in genes participating in the fatty acid burden of the liver in HFD-induced NAFLD. Notably, MCD mice, which are well known to display down-regulated de novo lipogenesis,22 showed a partial reconstitution of lipogenic

gene expression upon UDCA-LPE administration. We hypothesize that restoration of lipogenesis by UDCA-LPE may reflect a protective mechanism because lipids from de novo lipogenesis usually contain elongated and desaturated fatty acids, e.g., as a result of SCD1 action. These lipids are likely involved in improving cell membrane fluidity, hence GW-572016 datasheet protecting hepatocytes from injurious events such as ATM signaling pathway apoptosis.42 Further studies are under way to test this hypothesis. As for changes in metabolism, polyunsaturated fatty acids (PUFAs) have been implicated in fatty liver disease.4, 43 Recent data focusing on the plasma lipidomic profile of NAFLD patients found lower levels of essential PUFA linoleic acid (18:2 n6) and α-linoleic acid (18:3 n3) coincidental with a marked elevation of their downstream products, indicative of enhanced fatty acid desaturation due to action of Δ6DS.44 Along this line, in our study

we found a considerable increase in Δ5DS, Δ6DS, and ELOVL5 expression in HFD mice, which was down-regulated by UDCA-LPE to levels of control mice. It may be hypothesized that lower desaturase activity along the elongase pathway would result in less accumulation of arachidonic acid (20:4 n6) and therefore diminish the principal source for generation of proinflammatory prostaglandins45, 46 and nonenzymatic Niclosamide oxidation products.44 The potential implication for the effects of UDCA-LPE on PUFA metabolism needs further evaluation and is the subject of future studies. Despite the existing view that hepatic triglyceride accumulation constitutes the “first hit” of NAFLD,47 emerging data suggest that processing of excess free fatty acids to inert triglycerides may prevent lipotoxicity.48-50 Accordingly, earlier work found that inhibition

of triglyceride synthesis by blockade of DGAT2 improved hepatic steatosis, but worsened inflammation and fibrosis.51 The present analysis of changes in DGAT expression upon UDCA-LPE treatment indicated that the conjugate slightly increased DGAT1 and did not alter DGAT2 expression in HFD mice. Thus, improvement of hepatic steatosis by UDCA-LPE administration was not accomplished by an impairment of triglyceride synthesis. In summary, the results of the current study provide evidence that the bile acid–phospholipid conjugate UDCA-LPE ameliorates hepatic injury in different stages of NAFLD such as steatosis and advanced steatohepatitis. The conjugate has excellent anti-inflammatory characteristics, which further led to potent lipid-lowering properties, and may be capable of inhibiting disease progression.