Positional and temporal regulation of lipogenic gene expression in mouse liver

We have examined the dynamics of positional gene expression in mouse liver using the carbohydrate induction of lipogenic genes as a model. Using a protocol of fasting and refeeding a high-carbohydrate, no-fat diet to obtain maximal induction, we investigated the temporal expression and localization of malic enzyme (ME) and fatty acid synthase (FAS). In situ hybridization showed that both ME and FAS were expressed at low basal levels in all hepatocytes in livers of mice fed a control diet. Furthermore, dietary induction of ME and FAS mRNA occurred in periportal cells within 6 hours. After 12 hours, the portal cells were maximal; and after 24-36 hours, all cells showed high levels of message. This was coincident with expression of ME and FAS mRNAs, which appeared to be maximal between 24 and 36 hours. Both steady-state mRNA levels and pericentral localization then declined, until only periportal hepatocytes showed strong expression of ME and FAS. Nuclear transcription rates measured by run-on assay demonstrated that maximal transcription rates preceded maximum mRNA levels by peaking at 12 hours. Furthermore, run-on assays showed that the periportal induction by carbohydrates is primarily a transcriptional response for FAS, and both transcriptional and posttranscriptional for ME. These results indicate that lipogenic gene expression is a temporal response induced by carbohydrate feeding and is regulated by both positional and transcriptional mechanisms.