B01 Metabolic, molecular, and cell adhesion phenotypes in hepatocytes lacking huntingtin

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Abstract

Background

While Huntington’s disease (HD) is classically considered a neurological disorder, effects of the CAG repeat expansion in huntingtin (Htt) are not limited to the brain. HD patients experience a range of somatic signs including metabolic dysfunction, weight loss, and inflammation. Further, the huntingtin protein (HTT) is associated with a number of pathways involved in metabolic regulation. Our previous work suggests that while HttQ111/+ mice appear to have normal liver function at baseline, they show an inability to reorganize transcriptional and metabolic pathways to accommodate high-fat feeding. Predicting HTT loss-of-function liabilities is made difficult by the lack of a clear molecular definition of HTT’s normal biological roles, so in an effort to better understand wildtype huntingtin function, as well as determine whether loss of this function could underlie some of the pathology associated with peripheral signs in HD, we produced mice in which Htt is knocked out in the liver by crossing Httfl/fl mice with mice expressing Cre in hepatocytes.

Aims

Determine roles of wild-type huntingtin in the liver and effects of hepatic huntingtin knock-out.

Methods

We generated hepatocyte-specific Htt knock-out mice, which we termed LKOs. These mice were phenotyped with metabolic screens, histopathological analyses, electron microscopy, and molecular profiling including RNA sequencing, global- and huntingtin affinity-proteomics, 13C-tracer based metabolic flux, and global metabolomics.

Results

LKO mice appear grossly normal and reproduce at mendelian ratios, however they display reduced body weight, cell adhesion deficits, and an array of metabolic and molecular phenotypes.

Conclusions

The LKO mouse is a novel tool for uncovering huntingtin functions, as well as highlighting potential loss of function liabilities in HD.

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