Open AccessFarnesoid X Receptor Agonism, Acetyl‐Coenzyme A Carboxylase Inhibition, and Back Translation of Clinically Observed Endpoints of De Novo Lipogenesis in a Murine NASH Model
Author(s) -
Gapp Berangere,
Jourdain Marie,
Bringer Pauline,
Kueng Benjamin,
Weber Delphine,
Osmont Arnaud,
Zurbruegg Stefan,
Knehr Judith,
Falchetto Rocco,
Roma Guglielmo,
Dietrich William,
Valdez Reginald,
Beckmann Nicolau,
Nigsch Florian,
Sanyal Arun J.,
Ksiazek Iwona
Publication year - 2020
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1443
Subject(s) - farnesoid x receptor , lipogenesis , agonism , acetyl coa carboxylase , translation (biology) , chemistry , coenzyme a , smoothened , endocrinology , medicine , pharmacology , biochemistry , pyruvate carboxylase , nuclear receptor , hedgehog signaling pathway , enzyme , signal transduction , lipid metabolism , transcription factor , messenger rna , gene , politics , political science , law , reductase
A promising approach for the treatment of nonalcoholic steatohepatitis (NASH) is the inhibition of enhanced hepatic de novo lipogenesis (DNL), which is the synthesis of fatty acids from nonlipid sources. This study assesses three approaches to DNL suppression in a newly developed dietary NASH mouse model: i) dietary intervention (switch from NASH‐inducing diet to normal diet); ii) inhibition of acetyl‐coenzyme A carboxylase (ACC), the enzyme catalyzing the rate‐limiting step in DNL; and iii) activation of farnesoid X receptor (FXR), a major transcriptional regulator of DNL. C57BL/6J mice on a high‐fat diet combined with ad libitum consumption of a fructose–sucrose solution developed several of the liver histologic features seen in human disease, including steatosis, inflammation, and fibrosis, accompanied by elevated fibrosis biomarkers and liver injury enzymes. Obesity and metabolic impairments were associated with increased intestinal permeability and progression to adenoma and hepatocellular carcinoma. All three approaches led to resolution of established NASH with fibrosis in mice; however, some differences were noted, e.g., with respect to the degree of hepatic steatosis attenuation. While ACC inhibition resulted in elevated blood triglycerides and peripheral obesity, FXR activation prevented peripheral obesity in NASH mice. Comparative transcriptome analysis underlined the translatability of the mouse model to human NASH and revealed novel mechanistic insights into differential regulation of lipid, inflammatory, and extracellular matrix pathways by FXR agonism and ACC inhibition. Conclusion: Novel insights are provided on back translation of clinically observed endpoints of DNL inhibition by targeting ACC or FXR, which are promising therapeutic options for the treatment of NASH, in a newly developed diet‐induced NASH mouse model.