Elucidating the role of small heterodimer partner (SHP) in metabolism, injury and systemic disease

The Small Heterodimer Partner (SHP) regulates several metabolic processes, including bile acid levels, despite lacking the conserved DNA binding domain. While SHP is primarily studied as a downstream target of the Farnesoid X Receptor (FXR), its distinct hepatic role remains poorly understood. In this study, we report that liver-specific SHP knockout (LShpKO) mice exhibit impaired negative feedback of Cyp7a1 and Cyp8b1 upon bile acid challenge. Remarkably, a single copy of the SHP gene is sufficient to maintain this feedback response. LShpKO mice also show elevated total bile acid pools, with ileal bile acid composition resembling that of CA-fed control mice. Notably, agonistic activation of FXR (GW4064) in LShpKO mice did not alter the elevated basal expression of Cyp8b1 but did lower Cyp7a1 expression. Further, LShpKO livers display higher basal proliferation than those with functional SHP. Moreover, 33% of LShpKO mice aged 12-15 months developed hepatic tumors under basal conditions. Sequencing these livers uncovered alterations in cellular proliferation, lipid metabolism, oxidative stress, and amino acid metabolism compared to non-tumor-bearing aged LShpKO livers. To investigate the role of hepatic SHP in controlling cellular stress, we treated LShpKO animals with tunicamycin, a potent ER stress inducer. This treatment revealed that LShpKO animals exhibit higher levels of Atf4, paired with the decreased basal expression of Gorasp2, C6, and C9 under basal conditions. The association between these genes, our aged tumors, and increased basal proliferation suggests that SHP may mediate hepatic senescence and confer susceptibility to tumorigenesis after prolonged cellular stress exposure. Overall, our study highlights the critical role of SHP in maintaining bile acid homeostasis, regulating cellular stress responses, and preventing tumorigenesis in the liver.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Shaw, Ryan Philip Henry

Contributors dc:contributor

• Anakk, Sayeepriyadarshini
• Raetzman, Lori
• Nelson, Erik
• Wang, Bo

• Nuclear Receptors
• Bile Acids
• Proliferation
• Lipid Metabolism
• Er Stress
• Senescence

Statement dc:rights

• Copyright 2024 Ryan Shaw

Language dc:language

eng, en

Handle dc:identifier

https://hdl.handle.net/2142/127329

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F127329