Identification of a novel subset of hepatocytes that are simultaneously gluconeogenic and de novo lipogenic in the fed state and are naturally insulin resistant

In contrast, de novo lipogenesis (synthesis of fatty acids) is active in the fed state and is inactive in the fasted state. However, RNAPII ChIP-seq demonstrated that periportal but not pericentral hepatocytes display a basal (fed state) transcriptional activation of gluconeogenic genes that correlated with the basal level of gluconeogenic mRNA expression.

Targeted single cell RNA-seq, HCR RNA-FISH, and PrimeFlow identified a subpopulation of periportal hepatocytes (approximately 10% of total hepatocytes) that simultaneously co-express both gluconeogenic and lipogenic genes in the fed state. These dual-positive hepatocytes identified in normal mouse livers are also present in human hepatocytes from humanized mouse livers. Spatial metabolic imaging coupled with stable isotope tracing analyses at the single cell level demonstrated that these individual hepatocytes simultaneously undergo both gluconeogenesis and de novo lipogenesis.