Scientific Publications by FDA Staff

Am J Physiol Gastrointest Liver Physiol 2019 Jun 1;316(6):G720-34

Translational and transcriptional responses in human primary hepatocytes under hypoxia.

Hettiarachchi GK, Katneni UK, Hunt RC, Kames JM, Athey JC, Bar H, Sauna ZE, McGill JR, Ibla JC, Kimchi-Sarfaty C

The liver is the primary source of a large number of plasma proteins and plays a critical role in multiple biological processes. Inadequate oxygen supply characterizing various clinical settings such as liver transplantation exposes the liver to hypoxic conditions. Studies assessing hypoxia-induced global translational changes in liver are lacking. Here, we employed a recently developed ribosome profiling technique to assess global translational responses of human primary hepatocytes exposed to acute hypoxic stress (1% O2) for short term. In parallel, transcriptome profiling was performed to assess mRNA expression changes. We found that translational responses appeared earlier and were predominant over transcriptional responses. Significant decrease in translational efficiency of several ribosome genes indicated translational inhibition of new ribosome protein synthesis in hypoxia. Pathway enrichment analysis highlighted altered translational regulation of MAPK signaling, drug metabolism, oxidative phosphorylation and non-alcoholic fatty liver disease pathways. Gene ontology enrichment analysis revealed terms related to translation, metabolism, angiogenesis, apoptosis, and response to stress. Transcriptional induction of genes encoding heat shock proteins was observed within 30 minutes of hypoxia. Induction of genes encoding stress response mediators, metabolism regulators and pro-angiogenic proteins were observed at 240 minutes. Despite the liver being the primary source of coagulation proteins and implicated role of hypoxia in thrombosis, limited differences were observed in genes encoding coagulation associated proteins. Overall, our study demonstrates the predominance of translational regulation over transcription and highlighted differentially regulated pathways or biological processes in short-term hypoxic stress responses of human primary hepatocytes.