New zoning laws enforced by glucagon

Abstract

The liver exerts important systemic functions at multiple levels. Even though the tissue looks macroscopically uniform, it is very heterogeneous at the cellular level. Beyond hepatocytes, stellate cells, endothelial cells, and Kupffer cells, many additional cell types contribute to its architecture. Beyond the cellular heterogeneity, there is a significant degree of functional heterogeneity present within the tissue, with profound differences apparent with respect to the degree that different hepatocytes dedicate themselves to specific biochemical pathways. Which set of anabolic or catabolic pathways a hepatocyte commits itself to is not a stochastic process, however. Rather, there is a discrete spatial organization put in place, referred to as “liver zonation,” that is critically involved in the separation of different metabolic pathways (1). In PNAS, Cheng et al. (2) report that they have established an additional signaling axis within the liver, “the glucagon axis,” by which liver zonation becomes initiated and maintained. Hepatocytes within a functional liver unit, a hepatic lobule, assume distinct biochemical programs depending on their location. Blood flows from the portal vein and the hepatic artery through small blood vessels, referred to as sinusoids, to the central vein. While individual hepatocytes appear rather homogeneous along the axis, stretching from the periportal location (hepatic vein and hepatic artery) to the perivenous location (with the central vein), there are distinct differences within the microenvironment and biochemical properties of the cells themselves. The periportal region is exposed to nutrient- and oxygen-rich conditions. The portal vein supplies 75% of the blood supply to the liver and provides nutrients and hormones collected from the small intestine and much of the large intestine, the pancreas, and the spleen. The remaining 25% of the blood supply is contributed by the hepatic artery, which carries oxygen-rich blood (3). Together with the bile duct, these three vessels define the … [↵][1]1To whom correspondence should be addressed. Email: philipp.scherer{at}utsouthwestern.edu. [1]: #xref-corresp-1-1