P0959 - Diminished hepatic lipid synthesis accompanies reduced bile acid resorption after small bowel resection to promote dietary lipid malabsorption

Purpose
Following massive proximal small bowel resection (SBR), the remaining intestine undergoes adaptation, expanding nutritional absorptive capacity to prevent malabsorption, the major complication of short bowel syndrome (SBS). Adaptation reprograms the remaining ileum towards a jejunal identity, which could impair bile acid (BA) resorption, therefore, negatively affecting dietary lipid absorption. However, the liver may compensate for defects in BA resorption by increasing BA production to normalize lipid absorption. Therefore, we examined BA absorption, hepatic BA production, and dietary lipid uptake in response to SBR.

Methods
Male C57BL6 mice underwent a 50 or 75% proximal SBR, sham operation, or no operation. Four to eleven months later, serum BA, campesterol (dietary lipid plant sterol), and lathosterol (hepatic BA/cholesterol precursor) levels were measured. We also administered an oral gavage of a model fat, using fluorescent C16BODIPY. Hepatic triglyceride lipoprotein production was measured by administration of lipoprotein lipase inhibitor, poloxamer 407.

Results
BA and campesterol levels were 42% and >75% reduced after resection (Figure A, *p<0.05; Figure B, ANOVA **p<0.005), respectively. Uptake of oral C16BODIPY was 60% reduced in resected mice (Figure C, ****p<0.0001). Lathosterol levels failed to increase, but instead diminished, in 50% SBR mice (Figure D, ANOVA *p<0.05). Additionally, hepatic triglyceride production significantly decreased (Figure E, ANOVA ****p<0.0001).

Conclusion
We demonstrate that SBS leads to dietary fat malabsorption because the remaining bowel fails to absorb BAs normally, likely secondary to its jejunalization; furthermore, this deficit is not compensated by increased hepatic BA synthesis. Triglyceride secretion from the liver was reduced, suggesting global dysfunction of hepatic lipid metabolism. Thus, the major complications of SBS, malabsorption and intestinal-failure associated liver disease, decrease BAs by respective effects on resorption and synthesis. This prevents dietary lipid uptake, a problem that might be still further compounded by lymphatic defects that we previously reported after SBR.