Original ResearchFull Report: Basic and Translational—LiverLoss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol
Section snippets
Mice
C57BL/6 (control) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and F11r-/- mice were originally a gift from Dr Thomas N. Sato (Cornell University, New York, NY). F11r-/- mice were generated as previously described14 and were backcrossed to C57BL/6 mice for 7 generations. The intestine-specific JAM-A knockout mice, VillinCreF11rFL/FL, were obtained by crossing VillinCre mice with F11rFL/FL mice. C57BL/6, F11r-/-, F11rFL/FL, and VillinCreF11rFL/FL mice were bred and maintained
F11r-/- Mice Fed a HFCD Develop Severe Histologic Features of NASH Including Markers of Hepatic Fibrosis
To induce NAFLD, F11r-/- and control littermates were fed a HFCD for 8 weeks, F11r-/- and control mice fed a normal diet served as controls. While consumption of HFCD resulted in modest NAFL-related histologic findings in control mice, F11r-/- mice developed severe histologic features of NASH including ballooning degeneration of hepatocytes, inflammatory cell infiltration, and extensive pericentral, periportal, and sinusoidal fibrosis (Figure 1A, B, and F, and Supplementary Figure 1A and B). As
Discussion
In the current study, we provide experimental evidence that intestinal epithelial barrier function plays a major role in NAFLD progression. The HFCD-fed F11r-/- model overcomes key limitations that have hindered reliable induction of NASH along with typical features of the metabolic syndrome (MetS) in murine models even after long-term feeding. To date, investigators have struggled to reliably replicate MetS and typical features of human NASH in murine liver, including substantial evidence for
Acknowledgments
The authors acknowledge the contribution of graphic artist Deepali Gupta ([email protected]) for the generation of the summary figure 7.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by National Institutes of Health grant DK062092, VA grant I01BX001746, and funds from Emory University School of Medicine (F.A.A.), and the Emory University Integrated Cellular Imaging Microscopy Core of the Emory and Children's Pediatric Research Center.
Author names in bold designate shared co-first authorship.