Hepatic fat accumulation and changes in
lipid composition are hallmarks of
nonalcoholic fatty liver disease (
NAFLD). As an experimental approach for treatment of
NAFLD, we synthesized the
bile acid-
phospholipid conjugate
ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate in vitro and in vivo. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of
NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with
hyperlipidemia. In a second model, mice received a methionin-
choline-deficient (MCD) diet for up to 11 weeks, which induced advanced
nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by
intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in
alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum
triglyceride and
cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic
triglyceride and
cholesterol levels. Additionally, the conjugate lowered serum
caspase-8 activity in both models and decreased
lipid hydroperoxides in MCD mice. Abundance of proinflammatory
lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative
reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism.
CONCLUSION: The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of
NAFLD. By concurrently lowering hepatic
lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate
disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of
NAFLD.