Z Gastroenterol 2014; 52 - P_3_25
DOI: 10.1055/s-0033-1360944

Sequential PAT-expression in human hepatocyte steatosis

BK Straub 1, LM Pawella 1, M Hashani 1, E Eiteneuer 1, P Schirmacher 1
  • 1Ruprecht-Karls-University Heidelberg, University Clinic Heidelberg, Institute of Pathology, 69120 Heidelberg, Germany

Background & Aims: Hepatocellular steatosis is the most frequent liver disease in the western world and may develop further to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. We have previously shown that lipid droplet (LD)-associated proteins of the perilipin/PAT-family are differentially expressed in hepatocyte steatosis and that perilipin is de novo expressed. Aim of this study was to analyse the modalities of hepatocellular PAT-protein expression especially in relation to the recent development of steatosis and explore its diagnostic potential.

Methods: Immunohistochemical PAT-analysis was performed with over 120 liver biopsies of different etiology and duration of steatosis. Steatosis was induced in cultured hepatocytic cells with combinations of lipids, steatogenic substances and DMSO for up to 40 days together with stable downregulation of adipophilin and/or TIP47.

Results: Whereas perilipin and adipophilin were expressed in human chronic liver disease irrespective of the underlying etiology, in acute/toxic steatosis, TIP47, and MLDP were recruited from the cytoplasm to LDs, adipophilin was strongly increased, but perilipin was virtually absent. In long-term steatosis models in vitro, TIP47, MLDP, adipophilin, and finally perilipin were gradually induced at LDs of increasing size. Perilipin and associated LDs were intricately regulated on the transcriptional (PPARs, C/EBPs, SREBP), post-transcriptional (alternative splicing), and post-translational level (TAG-amount, LD-fusion). In long-term steatosis models under stable downregulation of adipophilin and/or TIP47, lipid droplets were reduced, but showed significantly larger sizes. Interestingly, MLDP, adipophilin and perilipin substituted for TIP47, and perilipin partly for adipophilin. Adipophilin was the major determinant of steatosis in vitro. In addition, perilipin facilitated lipolysis in vitro.

Conclusions: LD-maturation in hepatocytes in vivo and in vitro involves sequential expression of TIP47, MLDP, adipophilin and finally perilipin. Thus, PAT-proteins may be interesting diagnostic and therapeutic targets in human hepatocyte steatosis.