Ursodeoxycholyl Lysophosphatidyletanolamide (UDCA-LPE) modifies aberrant lipid profiles in non-alcoholic fatty liver disease

Hepatic fat accumulation with disturbed lipid homeostasis is a characteristic hallmark of non-alcoholic fatty liver disease (NAFLD). Previous work implicated a role for altered lipid composition in the pathophysiology of NAFLD. The bile-acid phospholipid conjugate Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a novel anti-inflammatory agent, which exerted hepatoprotective effects in murine high fat diet (HFD)-induced NAFLD with reduction of lipid overloading and suppression of de novo lipogenesis. The aim of the study was to perform lipidomic analysis in order to study changes in free fatty acid (FFA) and phospholipid levels and to detect variations in the fatty acid composition due to UDCA-LPE.

Results: Hepatic lipid extracts of HFD mice were analyzed by mass spectrometry. The results determined higher levels of total, saturated, mono- and diunsaturated FFA due to high fat diet, which were significantly decreased by UDCA-LPE. Detailed analysis of hepatic FFA composition revealed that this was predominantly attained by the reduction of the most abundant saturated and monounsaturated FFA species palmitic acid and oleic acid by UDCA-LPE. Unlike other FFA species, levels of LCPUFA, which are composed of arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were significantly increased in HFD mice upon UDCA-LPE treatment, which was mainly caused by elevated hepatic ARA pools. Accordingly, the product/precursor ratios for the n-3 and n-6 pathway, which serve as a measure for LCPUFA production from the essential fatty acids γ-linolenic acid and linoleic acid, were significantly increased in UDCA-LPE treated HFD mice. Further analysis of hepatic phospholipid classes and their molecular species showed a decrease in total phosphatidylcholine (PC), especially monounsaturated PC (PUFA-PC) levels in HFD mice. The loss of total PC due to high fat diet was significantly reversed by UDCA-LPE treatment by an increase in PUFA-PC pools, whereas saturated and monounsaturated PC levels were unchanged. Fatty acids, especially LCPUFA are able to influence lipid metabolism in the liver by modifying hepatic gene transcription. Therefore, we evaluated the effect of UDCA-LPE on the expression of PPARα, a key transcriptional regulator of fatty acid oxidation. Treatment with UDCA-LPE resulted in a significant upregulation of PPARα. Consistently, the expression of target genes downstream of PPARα such as CPT1α and AOX, which are crucially involved in mitochondrial and peroxisomal fatty acid oxidation, were significantly increased in HFD mice treated with UDCA-LPE.

Conclusion: UDCA-LPE is capable of modulating the defective fatty acid metabolism during experimental NAFLD thereby restoring altered lipid profiles in addition to its pronounced anti-inflammatory effects. Taken together, UDCA-LPE may be a promising drug candidate for the management of NAFLD.