D15: Dysregulated Lipid Metabolism is Associated with Progressive Liver Injury After Massive Small Bowel Resection in Murine Model

Presenter(s)

Evan Mayse

Abstract or Description

Background

Intestinal failure-associated liver disease (IFALD) is a morbid consequence of short gut syndrome (SGS), characterized by poor weight gain, diminished fat reserves, and liver steatosis. We use a murine surgical IFALD model to test the impact of small bowel resection (SBR) on liver de-novo lipogenesis (DNL).

Methods

8-week-old C57BL/6J Female mice (Jackson Labs, Bar Harbor, ME) underwent 75% SBR and sham operations and were randomized to 2-, 5-, and 10-week cohorts. All received liquid diet ad lib. Body composition (MRI), serum AST/ ALT, and liver histology were assessed. Fatty acid synthase (FASN) expression (via rt-qPCR) was used as a DNL marker. Two-way ANOVA or unpaired t-tests (p<0.05) were performed.

Results

Sham mice regained preoperative weight by two weeks, while SBR remained below preoperative weight (area under the curve analysis -0.9146 vs 1.513, p<0.0001). SBR mice exhibited decreased body fat composition with reciprocal increase in lean body mass. Serum AST and ALT were significantly increased at all timepoints compared to shams (p<0.05). Liver histology demonstrated progressive liver injury: macro-steatosis at five weeks and steatohepatitis at 10 weeks with hepatocyte ballooning and periportal inflammation. FASN expression was decreased at 2 and 5 weeks in SBR mice but increased at 10 weeks.

Conclusion

Our resection IFALD model shows progressive liver injury. Early-stage disease is associated with suppressed DNL, but advanced disease involves an upregulation of FASN. We believe this is an aberrant upregulation of FASN that may be secondary to the liver injury itself. Future multi-omic experiments will elucidate evolving regulation of lipid metabolism over time.