Liver Zonation – Revisiting Old Questions With New Technologies

Abstract

Despite the ever-increasing prevalence of non-alcoholic fatty liver disease (NAFLD), the etiology and pathogenesis remain poorly understood. This is due, in part, to the liver’s complex physiology and architecture. The liver maintains glucose and lipid homeostasis by coordinating numerous metabolic processes with great efficiency. This is made possible by the spatial compartmentalization of metabolic pathways a phenomenon known as liver zonation. Despite the importance of zonation to normal liver function, it is unresolved if and how perturbations to liver zonation can drive hepatic pathophysiology and NAFLD development. While hepatocyte heterogeneity has been identified over a century ago, its examination had been severely hindered due to technological limitations. Recent advances in single cell analysis and imaging technologies now permit further characterization of cells across the liver lobule. This review summarizes the advances in examining liver zonation and elucidating its regulatory role in liver physiology and pathology. Understanding the spatial organization of metabolism is vital to further our knowledge of liver disease and to provide targeted therapeutic avenues.

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

“…For example, gluconeogenesis, fatty acid β-oxidation, cholesterol synthesis, and ureagenesis are mainly considered to be performed by hepatocytes in the periportal region, where the oxygenated blood is transported via hepatic arteries, whereas glycolysis, DNL, bile acid synthesis, and xenobiotic detoxification occur in the pericentral region, which is relatively hypoxic [ 59 , 60 ]. Dysregulation of metabolic zonation is considered to lead to the development of lifestyle-related diseases such as obesity, diabetes, and NAFLD [ 61 , 62 ]. In fact, NAFLD is considered to begin with pericentral steatosis and inflammation with periportal inflammation and fibrosis considered late-occurring histological lesions [ 63 ].…”

Dual Cre and Dre recombinases mediate synchronized lineage tracing and cell subset ablation in vivo

“…The mammalian liver has remarkable regenerative capability after injury. The hepatocytes of the liver lobule are heterogeneous in gene expression, proliferation rate, and metabolic functions ( 54 , 55 , 56 ). For example, peri-central hepatocytes express CYP2E1 and execute glycolysis and drug metabolism, while peri-portal hepatocytes express MFSD2A and execute gluconeogenesis and ammonia detoxification ( 41 ).…”

LKB1 acts as a critical brake for the glucagon-mediated fasting response

“…Hepatocytes shift between glucose uptake for storage and efflux during fed and fasted states, respectively. Despite the fact that glucose uptake, storage and efflux are differentially regulated across the hepatic lobule 12, 13 , it is not clear if LKB1 is involved and how. To measure the changes in glucose uptake and release, we developed an IVM-based assay to measure glucose mobilization in space and time 24 .…”

“…demonstrated that glucagon is also involved in the spatial regulation of hepatic metabolism 9,10 . The spatial segregation of hepatic metabolism, also known as liver zonation, permits simultaneous operation of conflicting pathways [11][12][13] . This is achieved through the organization of hepatocytes in polarized, hexagonal lobules in which six portal vessels deliver oxygen, nutrients, and hormones (Sup Fig 1B) that flow directionally towards a single central vein.…”