Metabolic function of a novel Dual-Modal hepatocyte

About This Grant

The mammalian liver is composed of parenchymal (hepatocytes) and non- parenchymal (endothelial, kupffer, cholangiocytes, stellate) cells organized into repetitive hexagonal arrays termed lobules. Within each lobule the hepatocytes are distributed from the portal triad (portal vein, hepatic artery, bile duct) at the six vertices of the hexagon and the central vein located at the centroid. The hepatocytes aligned within a lobule display functionally distinct metabolic properties and are generally divided into three zones, the periportal hepatocytes (zone 1), middle hepatocytes (zone 2) and the pericentral hepatocytes (zone 3). Many studies have further shown that the hepatocytes have distinct functions across the periportal to pericentral spatial axis across each individual lobule. One important liver metabolic function is gluconeogenesis that is a dynamically regulated process controlled by numerous hormones and metabolic inputs. During our investigation of the temporal and spatial regulation of gluconeogenesis, we observed that there is a distinct basal (fully fed) state of active gluconeogenesis restricted to periportal hepatocytes. Further investigation has revealed the presence of a novel subset of periportal hepatocytes (termed Dual-Modal hepatocytes) that express both gluconeogenic and lipogenic genes in the fed state, suggesting that these cells are naturally resistant to suppression of either gluconeogenic activity or gluconeogenic gene expression by insulin. These data provide the unexpected conclusion that normal livers have a unique subset of hepatocytes that remain gluconeogenic in the fed state and have the capacity to simultaneously express lipogenic genes and undergo de novo lipogenesis. These findings open the paradigm-shifting possibility that hepatic insulin resistance may not necessarily arise from an induction of cellular insulin resistance but alternatively from the expansion (proliferation) in the number of these pre-existing insulin-resistant hepatocytes. Using integrative physiologic approaches coupled with various single cell technologies coupled with stable isotope metabolic spatial imaging, we propose a series of studies to unravel the physiologic and pathophysiologic role of these Dual-Modal hepatocytes.