Western-diet enhances expression of death receptors and fatty acid transporters in a mouse model of 70% hepatectomy and leads to increased cell proliferation in the liver

Aims: The non-alcoholic fatty liver disease (NAFLD) is associated with excessive lipid-droplet accumulation in hepatocytes, increased death-receptor expression, altered apoptosis-induction and may progress to liver damage and fibrosis. Active transport of free fatty acids (FFA) is thought to participate in liver cell damage and enhanced apoptosis sensitivity. Death Receptors (DR) apart from apoptosis signalling, also initiate cell proliferation. Thus we investigated, whether high fat diet (HFD) has an impact on apoptosis or regeneration after hepatectomy. Methods: C57Bl/6J-mice received standard (SD) or HFD for 6 weeks, underwent 70% partial hepatectomy (Phx) and were sacrificed on postoperative day (POD) 1, 2 or 7. mRNA expression of FABP-1, FATP-5, CD36/FAT, CD95/Fas, TNFR-1, NOXA and cFLIPL were investigated by qrt-PCR. Proliferation after 70% PHx was visualized by Ki-67 immunhistochemistry. Results: HFD enhanced DR-expression after 70% PHx compared to SD-animals (i.e. CD95/Fas: POD2: x5.53±1.63, p=0.03; TNFR-1: POD1: x27.48±3 .77, p<0.001). Postoperative expression of fatty acid transporters were elevated by HFD (FABP-1: x3.8 5±0.8; p=0.002; CD36/FAT POD1: x3.68±0 .72, p=0.01; POD2: x17.65±3.06, p=0.003; FATP-5 POD2: HFD x3.9±0.77; p=0.013). Ki-67-staining showed increased liver cell proliferation in HFD-mice after PHx compared to SD-mice (POD1: 3% vs. 0.3%, p<0.0001; POD2: 52% vs. 34%; p=0.0002). Conclusion: Data of a mouse model of hepatectomy show increased mRNA expression of FFA-transport proteins, DR’s and elevated cell-proliferation after 70% PHx. FFA may thus pose a risk by increasing cellular susceptibility to apoptosis in general, but could have a beneficial effect in regeneration after hepatectomy.