The Impact of High Fat Diet on Hepatic Spatial Heterogeneity in Murine Model

Abstract

Introduction Non-Alcoholic Fatty Liver Disease (NAFLD)is characterized by progressive accumulation of hepatocellular fat possibly associated with impaired hepatic autophagy function. Our preliminary observation showed altered liver zonation in autophagy-defective conditions. Whether liver zonation is altered in the condition of NAFLD and whether it has any pathological role in disease progression is unknown. In this study, we used a dietary mouse model of NAFL to examine the status of liver zonation and the signaling pathways regulating the hepatic zonation. Methods Wild type mice were fed a High Fat Diet (HFD) for a duration of 24 weeks with liver samples taken at 1 week, 10 weeks, and 24 weeks. Zonal markers were examined at mRNA and protein level by quantitative polymerase chain reaction and Western blotting. Results We identified significant downregulation of various pericentral markers such asCyp2e1, Cyp1a2, Glul, Oat, and Rhbg. Further investigation into the Cytochrome 450 superfamily of monooxygenases, which are pericentral localized proteins, demonstrated marked downregulation of different Cyp450 genes suggesting that xenobiotics handling may be impaired in HFD fed mice. On the other hand, upregulation of periportal markers such as Cdh1, Gls2, Ctnnbip1 were noted in the HFD liver. Kinetics analysis of periportal markers such as E-cadherin showed elevated expression as early as 1 week of HFD feeding. Examination of Wnt/β- catenin signaling pathway, which defines pericentral metabolic zonation, showed no remarkable changes in expression of Wnt/β-catenin downstream target genes. Contrary to our expectations, expression of HNF4α which is responsible for the regulation of periportal genes expression was remarkably downregulated at both protein and mRNA level despite elevated pericentral zonal genes. Conclusions We demonstrate that HFD altered the expression of selective periportal and pericentral zonal markers suggesting that HFD has an impact on hepatic spatial heterogeneity in a murine model. As such an observed alteration in the zonation of the HFD liver suggests that the metabolic processes which require zonated conditions may also be altered. HFD mediate downregulation of HNF4α may have an important role in the disturbance of hepatic zonation and disease pathogenesis.