Influence of Liver Fibrosis on Lobular Zonation

Abstract

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

The Genetic Architecture of Carbon Tetrachloride-Induced Liver Fibrosis in Mice

“… 26 MUPs were also recently reported to be some of the most down-regulated genes in response to CCl 4 treatment of male C57BL/6N mice. 27 Various solute carrier family members including glutamate transporter 1 ( Slc1a2 ) and organic cation transporter ( Slc22a3 ) were also markedly down-regulated. A number of highly up-regulated genes are suggestive of HSC and macrophage involvement: macrophage metalloproteinase Mmp2 , a receptor for the innate immune system ( Trem2 ), type 1 transmembrane glycoprotein ( Gpnmb ), and a type 1 collagen ( Col1a1 ), the major component of fibrosis produced only by activated HSCs.…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

“…The Special Issue includes novel findings of important anatomic aspects of liver fibrosis. Ghallab et al used a toxic (carbon tetrachloride for 2, 6, and 12 months) a surgical (bile duct ligation for 21 days) and a genetic (Mdr2 −/− ) mouse model to investigate how liver fibrosis influences lobular zonation [53]. The authors carried out an extensive set of experiments and come to the conclusion that liver fibrosis of different etiologies leads to periportalization of liver lobules that occurs as a common response to percentral and also periportal damage [53].…”

“…Ghallab et al used a toxic (carbon tetrachloride for 2, 6, and 12 months) a surgical (bile duct ligation for 21 days) and a genetic (Mdr2 −/− ) mouse model to investigate how liver fibrosis influences lobular zonation [53]. The authors carried out an extensive set of experiments and come to the conclusion that liver fibrosis of different etiologies leads to periportalization of liver lobules that occurs as a common response to percentral and also periportal damage [53]. Significantly, by use of functional genomics, the authors were able to compile a consensus list of periportal and pericentral genes that are relevant in mediating metabolic zonation.…”

Hepatotoxicity of anesthetic gases

“…using primary human hepatocytes (Godoy et al, 2013[ 4 ]; Albrecht et al, 2019[ 1 ]; Gu et al, 2018[ 7 ]; Grinberg et al, 2014[ 6 ], 2018[ 5 ]). In animal models often the toxic solvent CCl 4 (Hoehme et al, 2010[ 8 ]; Ghallab et al, 2016[ 2 ]) or acetaminophen (Ghallab et al, 2019[ 3 ]; Leist et al, 2017[ 12 ]) are used to study hepatotoxicity. In human liver diseases as well as in animal studies with experimental, e.g.…”