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. 2020 May;13(3):529-538.
doi: 10.1111/cts.12735. Epub 2020 Jan 25.

A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death

François Briand  1 , Christophe Heymes  2 , Lucile Bonada  1 , Thibault Angles  2 , Julie Charpentier  2 , Maxime Branchereau  2 , Emmanuel Brousseau  1 , Marjolaine Quinsat  1 , Nicolas Fazilleau  3 , Rémy Burcelin  2 , Thierry Sulpice  1
Affiliations

A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death

François Briand et al. Clin Transl Sci. 2020 May.

Abstract

The long duration of animal models represents a clear limitation to quickly evaluate the efficacy of drugs targeting nonalcoholic steatohepatitis (NASH). We, therefore, developed a rapid mouse model of liver inflammation (i.e., the mouse fed a high-fat/high-cholesterol diet, where cyclodextrin is co-administered to favor hepatic cholesterol loading, liver inflammation, and NASH within 3 weeks), and evaluated the effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist elafibranor (ELA). C57BL6/J mice were fed a 60% high-fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX diet) for 3 weeks. After 1 week of the diet, mice were treated orally with vehicle or ELA 20 mg/kg q.d. for 2 weeks. Compared with vehicle, ELA markedly reduced liver lipids and nonalcoholic fatty liver disease activity scoring, through steatosis, inflammation, and fibrosis (all P < 0.01 vs. vehicle). Flow cytometry analysis showed that ELA significantly improved the HFCC/CDX diet-induced liver inflammation by preventing the increase in total number of immune cells (CD45+), Kupffer cells, dendritic cells, and monocytes population, as well as the reduction in natural killer and natural killer T cells, and by blocking conversion of T cells in regulatory T cells. ELA did not alter pyroptosis (Gasdermin D), but significantly reduced necroptosis (cleaved RIP3) and apoptosis (cleaved caspase 3) in the liver. In conclusion, ELA showed strong benefits on NASH, including improvement in hepatic inflammation, necroptosis, and apoptosis in the 3-week NASH mouse. This preclinical model will be useful to rapidly detect the effects of novel drugs targeting NASH.

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Conflict of interest statement

F.B., L.B., E.B., M.Q., and T.S. are employees of Physiogenex. F.B., R.B., and T.S. declare shares in Physiogenex. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Hematoxylin and eosin and Sirius red stained liver section in mice fed a chow or a 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX) diet for 1‐week at ×10 (a) and ×20 (b) magnification. Black squares localize the area of the ×20 magnification shown in panel b. Dashed white squares indicate liver steatosis and inflammatory foci.
Figure 2
Figure 2
Hematoxylin and eosin and Sirius red stained liver sections at ×10 (a) and ×20 (b) magnification, in 3‐week 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water diet fed mice treated orally with vehicle or elafibranor 20 mg/kg q.d. for 2 weeks. Black squares localize the area of the ×20 magnification shown in panel (b). Dashed white squares indicate liver steatosis and inflammatory foci, blue arrows indicate portal fibrosis.
Figure 3
Figure 3
Quantification of liver immune cells by flow cytometry analysis in mice fed with a chow or a 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet (HFCC) diet for 1‐week or HFCC with 2% cyclodextrin in drinking water (CDX) fed mice treated with vehicle or elafibranor for 2 weeks: total CD45+ cell counts (a), F4/80+ Kupffer cells (b), CD68+ phagocytic Kupffer cells (c), CX3CR1+ monocytes (d), CD11c+ conventional dendritic (CD) cells (e), CD8a+ conventional dendritic cells 1 (f), NK1.1+ TCRab‐ natural killer (NK) cells (g), NK1.1+ TCRab+ NK T cells (h), TCRgd+ γδ T cells (i), CD19+ B220+ B cells (j), CD4+/CD8+ T cells (k), CD8+ cytotoxic T lymphocytes (l), FoxP3+ regulatory T lymphocytes (m), and CD4+ helper T lymphocytes (n). Data are shown as mean ± SEM, n = 8–10 per group. *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 4
Figure 4
Western blots (a) and protein levels of hepatic cleaved receptor interacting protein 3 (RIP‐3), cleaved caspase 3, and actin from 3‐week 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX) diet fed mice treated orally with vehicle or elafibranor 20 mg/kg q.d. for 2 weeks. Data are shown as mean ± SEM, n = 6 per group. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. vehicle.
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