Formulating elafibranor and obeticholic acid with phospholipids decreases drug-induced association of SPARC to extracellular vesicles from LX-2 human hepatic stellate cells

Eur J Pharm Biopharm. 2023 Jan;182:32-40. doi: 10.1016/j.ejpb.2022.11.025. Epub 2022 Dec 2.

Abstract

Chronic hepatic diseases often compromise liver function and are directly responsible for up to two million yearly deaths world-wide. There are yet no treatment options to solve this global medical need. Experimental drugs elafibranor (Ela) and obeticholic acid (OA) appeared promising in numerous earlier studies, but they recently struggled to show significant benefits in patients. Little is known on the drugs' impact on hepatic stellate cells (HSCs), key players in liver fibrogenesis. We recently reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs, including differences in their extracellular vesicles (EVs). Here, we newly formulated Ela and OA in PPC liposomes and evaluated their performance on the LX-2 (human HSC) cell line through our rigorous methods of EV-analysis, now expanded to include lipidomics. We show that direct treatments with Ela and OA increase EV-associated secreted protein acidic and cysteine rich (SPARC), a matricellular protein overexpressed in fibrogenesis. However, our results suggest that this potentially damaging drugs' action to HSCs could be mitigated when delivering them with lipid-based formulations, most notably with a PPC-rich phospholipid inducing specific changes in the cellular and EV phospholipid composition. Thus, EV analysis substantially deepens evaluations of drug performances and delivery strategies.

Keywords: Elafibranor; Extracellular vesicles; Obeticholic acid; Phospholipids; Polyenylphosphatidylcholines; SPARC.

MeSH terms

  • Extracellular Vesicles* / metabolism
  • Hepatic Stellate Cells*
  • Humans
  • Liver Cirrhosis / drug therapy
  • Osteonectin / metabolism
  • Phospholipids / metabolism

Substances

  • 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid
  • Phospholipids
  • obeticholic acid
  • SPARC protein, human
  • Osteonectin