Mode of action of the bile-acid phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) on fatty acid uptake in hepatocytes: implication for its therapeutic use in non-alcoholic steatohepatitis (NASH).

• Applicant: Professor Dr. Wolfgang Stremmel
• Subject Area: Gastroenterology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 134226865

Non-alcoholic steatohepatitis (NASH) is a common metabolic liver disease with doubtful prognosis. The natural cause of the disease is determined by its progression to cirrhosis. Until this date no effective therapy for NASH is available. Therefore we designed a potentially effective drug candidate which is comprised of a phosphatidylcholine precursor, lysophosphatidyletanolamine, and ursodeoxycholic acid (UDCA-LPE). Lysophosphatidyletanolamine (LPE) is a phospholipid which intracellulary is converted to phosphatidylcholin (PC). The rationale for induction of an increase of PC uptake into the liver is derived from the fact that hepatic PC levels are decreased in NASH. PC exerts cytoprotective effects by stabilizing membranes and inhibiting apoptosis. Therefore, it seems logical to supplement for depleted PC as a strategy to treat NASH. For the selective enrichment of LPE in the liver, it was coupled to UDCA which is specifically taken up by hepatocytes via bile salt carrier systems. Accordingly, in preceding experiments it was shown that also the UDCA-LPE conjugate was effectively targeted to the liver. Here it was hydrolyzed to UDCA and LPE which can be metabolized to PC. In cell culture experiments it was demonstrated that UDCA-LPE is protective during cell starvation and TNFα-induced apoptosis. Detailed analyses revealed that UDCA-LPE as an intact conjugate can even be more cytoprotective than its hydrolyzed components. In this DFG application it is planned to pursue more extensive in vivo studies to investigate the prosurvival pathways and anti-inflammatory effects of UDCA-LPE. As an experimental model we chose primary rat hepatocytes where injury will be induced by a mixture of free fatty acids or by methionine- and choline-deficiency (MCD) in the culture medium. Furthermore, the cytoprotective and anti-inflammatory effects of UDCA-LPE in vivo will be investigated using two NASH mouse models: mice on MCD diet and mice on a high-fat diet. These experiments are the basis for evaluation of the efficacy of UDCA-LPE for treatment of NASH in men at the level of clinical trials.

• DFG Programme: Research Grants