Validation of tissue expression and exploration of metabolic phenotypes in hepatocyte-specific huntingtin knockout mice
Research Mentor(s)
Carroll, Jeffrey B. (Jeffrey Bryan), 1977-
Description
Huntington’s disease (HD) is traditionally viewed as a neurodegenerative disease, despite the ubiquitous presence of the causal agent, expanded polyglutamine huntingtin protein (HTT), throughout the body. HD patients can display an array of peripheral symptoms, including metabolic disorders such as weight loss and malabsorption. Further, an understanding of the myriad roles for huntingtin in normal cellular function remains incomplete. In order to better understand the role huntingtin in metabolism, we produced mice in which HTT has been knocked out in hepatocytes (LKO mice). Here we show that LKO mice are born at the expected Mendelian ratio, with western blots confirming that huntingtin knockout is limited to the liver. We find that LKO mice appear grossly normal, but exhibit decreased body weight and length compared to age-matched wildtype mice. We also present results of metabolic phenotyping, including glucose tolerance and insulin tolerance testing. This work contributes to an understanding of the role huntingtin plays in metabolism and raises important safety considerations for HTT lowering therapies targeting the periphery.
Document Type
Event
Start Date
15-5-2019 9:00 AM
End Date
15-5-2019 5:00 PM
Location
Carver Gym (Bellingham, Wash.)
Department
Behavioral Neuroscience
Genre/Form
student projects, posters
Subjects – Topical (LCSH)
Huntington's disease--Research
Type
Image
Rights
Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this document for commercial purposes, or for financial gain, shall not be allowed without the author’s written permission.
Language
English
Format
application/pdf
Validation of tissue expression and exploration of metabolic phenotypes in hepatocyte-specific huntingtin knockout mice
Carver Gym (Bellingham, Wash.)
Huntington’s disease (HD) is traditionally viewed as a neurodegenerative disease, despite the ubiquitous presence of the causal agent, expanded polyglutamine huntingtin protein (HTT), throughout the body. HD patients can display an array of peripheral symptoms, including metabolic disorders such as weight loss and malabsorption. Further, an understanding of the myriad roles for huntingtin in normal cellular function remains incomplete. In order to better understand the role huntingtin in metabolism, we produced mice in which HTT has been knocked out in hepatocytes (LKO mice). Here we show that LKO mice are born at the expected Mendelian ratio, with western blots confirming that huntingtin knockout is limited to the liver. We find that LKO mice appear grossly normal, but exhibit decreased body weight and length compared to age-matched wildtype mice. We also present results of metabolic phenotyping, including glucose tolerance and insulin tolerance testing. This work contributes to an understanding of the role huntingtin plays in metabolism and raises important safety considerations for HTT lowering therapies targeting the periphery.