Feeding-Induced Discordance: Protein-mRNA Correlation Varies by Zone, Sex, and Fasting in Mouse Hepatocytes

The mammalian liver plays an essential role in maintaining metabolic homeostasis in response to fasting and feeding. Additionally, the liver exhibits sex dimorphism and zonation. To investigate how these factors interact, we performed RNA-seq and proteomics on periportal and pericentral hepatocytes isolated from male and female mice under fed and starved conditions. We developed a classification system to assess protein-mRNA relationship and found that most zonation genes showed strong concordance between mRNA and protein. Classical growth hormone regulated sex-biased genes also exhibited concordance, while a significant subset of sex genes showed protein-level bias without corresponding mRNA differences. Transition between feeding and starvation triggered widespread changes in mRNA expression alongside rapid modulation of functional de novo lipogenesis. However, key lipogenic enzymes—such as ACC, ACLY, and FAS —showed little to no corresponding change at the protein level. To facilitate further exploration of these findings, we developed Discorda, a web-based database for interactive data analysis. Our findings reinforce the principle that mRNA changes do not reliably predict corresponding protein levels (and vice versa), particularly in the context of sex and acute metabolic regulation. Mice were trained for 3 days by removing food at 5PM and feeding at 9:00 the next day (16h fasting overnight and 8h feeding daytime). On the day of experiment, mice were provided food with drinking water that contained 20% of sucrose. The fed (0h) mice were sacrificed at 13:00 equal to 4h of feeding (0h). For fasted mice, the food and sucrose water were taken out at 13:00, then sacrificed at 13:00 the next day for fast 24h (24h).