TY - JOUR
T1 - Liver injury after small bowel resection is prevented in obesity-resistant 129S1/ SvImJ mice
AU - Onufer, Emily J.
AU - Han, Yong Hyun
AU - Courtney, Cathleen
AU - Steinberger, Allie
AU - Tecos, Maria
AU - Sutton, Stephanie
AU - Sescleifer, Anne
AU - Ou, Jocelyn
AU - Czepielewski, Rafael Sanguinetti
AU - Randolph, Gwendalyn J.
AU - Warner, Brad W.
N1 - Funding Information:
This work was supported by The Digestive Diseases Research Core Center of the Washington University School of Medicine (NIH No. P30DK52574), the Children’s Surgical Sciences Research Institute of the St. Louis Children’s Hospital Foundation, NIH DP1DK109668 (to G. J. Randolph), the Immunology Training Grant NIH T32 AI007163 (to Y-H. Han, R. Sanguinetti Czepielewski), NIAID Primary Caregiver Award R37 AI049653 20S1 (to G. J. Randolph, E. J. Onufer), and the Department of Pediatrics Training Grant NIH T32 DK077653 (E. J. Onufer).
Publisher Copyright:
© 2021 the American Physiological Society
PY - 2021/5
Y1 - 2021/5
N2 - Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARa expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARa and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome. NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARa and TLR4 in C57BL/6 mice with short bowel syndrome.
AB - Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARa expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARa and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome. NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARa and TLR4 in C57BL/6 mice with short bowel syndrome.
KW - Intestinal failure-associated liver disease
KW - Short bowel syndrome
KW - Small bowel resection
UR - http://www.scopus.com/inward/record.url?scp=85106539329&partnerID=8YFLogxK
U2 - 10.1152/AJPGI.00284.2020
DO - 10.1152/AJPGI.00284.2020
M3 - Article
C2 - 33729834
AN - SCOPUS:85106539329
SN - 0193-1857
VL - 320
SP - G907-G918
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 5
ER -