Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes

Abstract

Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.

A genetic hypothesis for burnt‐out steatohepatitis

“…Limitations of the Ng et al work include (a) the low number of individuals and the limited spectrum of disease surveyed, precluding generalisation of the results; (b) the lack of understanding on how the S22W FOXO1 mutation arises in relation to specific drivers of liver disease; and, most importantly, (c) demonstration of a causal relationship between the FOXO1 S22W mutation and the decrease in hepatic fat typical of fibrosis progression, and evaluation of the impact on pathways underlying disease progression 28 …”

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 ].…”

Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair

“…However, as the insult progresses, steatosis and then steatohepatitis become pan-zonal. These differences, especially during the early stages of the disease, may be due to initial perturbations that have been previously ignored and that, if identified, can help in devising specific preventive strategies 31 . Likewise, due to the zonated expression of several xenobiotic metabolism–related genes, such as cytochrome P450s, including 2E1, alcohol-induced liver injury is mostly pericentral as well 32 .…”