Intestinal Knockout of Peroxisome Proliferator-Activated Receptor-Alpha Affects Structural Adaptation but Not Liver Injury Following Massive Enterectomy

Overview

Journal J Pediatr Surg

Specialties General Surgery
Pediatrics

Date 2023 Mar 15

PMID 36922278

Authors

Hannah M Phelps

Kerry A Swanson

Allie E Steinberger

Jun Guo

Ashley C King

Chidananda Mudalagiriyappa Siddappa

Nicholas O Davidson

Deborah C Rubin

Brad W Warner

Affiliations

Soon will be listed here.

Abstract

Background: Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of intestinal lipid transport and metabolism whose expression is selectively increased after SBR. Here we asked if attenuating intestinal PPARα signaling would prevent steatosis and liver injury after SBR.

Methods: Pparα was deleted selectively in adult mouse intestine using a tamoxifen-inducible Cre-LoxP breeding schema. Mice underwent 50% SBR. At 10 weeks post-operatively, metabolic phenotyping, body composition analysis, in vivo assessment of lipid absorption and intestinal permeability, and assessment of adaptation and liver injury was completed.

Results: Pparα intestinal knockout and littermate control mice were phenotypically similar in terms of weight trends and body composition after SBR. All mice demonstrated intestinal adaptation with increased villus height and crypt depth; however, Pparα intestinal knockout mice exhibited decreased villus growth at 10 weeks compared to littermate controls. Liver injury and fibrosis were similar between groups as assessed by serum AST and ALT levels, Sirius Red staining, and hepatic expression of Col1a1 and Acta2.

Conclusions: Inducible intestinal deletion of Pparα influences structural adaptation but does not mitigate liver injury after SBR. These findings suggest that enterocyte PPARα signaling in adult mice is dispensable for resection-induced liver injury. The results are critical for understanding the contribution of intestinal lipid metabolic signaling pathways to the pathogenesis of hepatic injury associated with short bowel syndrome.

References

Onufer E, Czepielewski R, Seiler K, Erlich E, Courtney C, Bustos A . Lymphatic network remodeling after small bowel resection. J Pediatr Surg. 2019; 54(6):1239-1244. PMC: 6545263. DOI: 10.1016/j.jpedsurg.2019.02.026. View

Estrada-Meza J, Videlo J, Bron C, Saint-Beat C, Silva M, Duboeuf F . Tamoxifen Treatment in the Neonatal Period Affects Glucose Homeostasis in Adult Mice in a Sex-Dependent Manner. Endocrinology. 2021; 162(7). DOI: 10.1210/endocr/bqab098. View

Stojanovic O, Altirriba J, Rigo D, Spiljar M, Evrard E, Roska B . Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα. Nat Commun. 2021; 12(1):7031. PMC: 8639731. DOI: 10.1038/s41467-021-27133-7. View

Squires R, Duggan C, Teitelbaum D, Wales P, Balint J, Venick R . Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr. 2012; 161(4):723-8.e2. PMC: 3419777. DOI: 10.1016/j.jpeds.2012.03.062. View

Mashek D, Li L, Coleman R . Long-chain acyl-CoA synthetases and fatty acid channeling. Future Lipidol. 2011; 2(4):465-476. PMC: 2846691. DOI: 10.2217/17460875.2.4.465. View

Yan T, Luo Y, Yan N, Hamada K, Zhao N, Xia Y . Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis. Hepatology. 2022; 77(1):239-255. PMC: 9970020. DOI: 10.1002/hep.32538. View

Courtney C, Warner B . Pediatric intestinal failure-associated liver disease. Curr Opin Pediatr. 2017; 29(3):363-370. DOI: 10.1097/MOP.0000000000000484. View

Kelly D . Liver complications of pediatric parenteral nutrition--epidemiology. Nutrition. 1998; 14(1):153-7. DOI: 10.1016/s0899-9007(97)00232-3. View

Beath S, Davies P, Papadopoulou A, Khan A, Buick R, Corkery J . Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg. 1996; 31(4):604-6. DOI: 10.1016/s0022-3468(96)90507-2. View

10.

Tantemsapya N, Meinzner-Derr J, Erwin C, Warner B . Body composition and metabolic changes associated with massive intestinal resection in mice. J Pediatr Surg. 2008; 43(1):14-9. DOI: 10.1016/j.jpedsurg.2007.09.010. View

11.

Barron L, Bao J, Aladegbami B, Colasanti J, Guo J, Erwin C . Toll-like receptor 4 is critical for the development of resection-associated hepatic steatosis. J Pediatr Surg. 2017; 52(6):1014-1019. PMC: 5466889. DOI: 10.1016/j.jpedsurg.2017.03.026. View

12.

Chang M, Puder M, Gura K . The use of fish oil lipid emulsion in the treatment of intestinal failure associated liver disease (IFALD). Nutrients. 2013; 4(12):1828-50. PMC: 3546610. DOI: 10.3390/nu4121828. View

13.

Engelstad H, Barron L, Moen J, Wylie T, Wylie K, Rubin D . Remnant Small Bowel Length in Pediatric Short Bowel Syndrome and the Correlation with Intestinal Dysbiosis and Linear Growth. J Am Coll Surg. 2018; 227(4):439-449. PMC: 6162148. DOI: 10.1016/j.jamcollsurg.2018.07.657. View

14.

Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos W, Pakarinen M . Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. JPEN J Parenter Enteral Nutr. 2015; 41(2):238-248. DOI: 10.1177/0148607115584388. View

15.

Shim J, Moulson C, Newberry E, Lin M, Xie Y, Kennedy S . Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice. J Lipid Res. 2008; 50(3):491-500. PMC: 2638106. DOI: 10.1194/jlr.M800400-JLR200. View

16.

Onufer E, Han Y, Czepielewski R, Courtney C, Sutton S, Randolph G . Effects of high-fat diet on liver injury after small bowel resection. J Pediatr Surg. 2020; 55(6):1099-1106. PMC: 7299751. DOI: 10.1016/j.jpedsurg.2020.02.037. View

17.

Hojan K, Molinska-Glura M, Milecki P . Physical activity and body composition, body physique, and quality of life in premenopausal breast cancer patients during endocrine therapy--a feasibility study. Acta Oncol. 2012; 52(2):319-26. DOI: 10.3109/0284186X.2012.744468. View

18.

Hesselbarth N, Pettinelli C, Gericke M, Berger C, Kunath A, Stumvoll M . Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice. Biochem Biophys Res Commun. 2015; 464(3):724-9. DOI: 10.1016/j.bbrc.2015.07.015. View

19.

Lee S, Pineau T, Drago J, Lee E, Owens J, Kroetz D . Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995; 15(6):3012-22. PMC: 230532. DOI: 10.1128/MCB.15.6.3012. View

20.

Bishay M, Pichler J, Horn V, MacDonald S, Ellmer M, Eaton S . Intestinal failure-associated liver disease in surgical infants requiring long-term parenteral nutrition. J Pediatr Surg. 2012; 47(2):359-62. DOI: 10.1016/j.jpedsurg.2011.11.032. View