# Huntingtin knockdown dysregulates autophagic degradation of Apolipoprotein E

## TL;DR

Reducing the HTT protein in liver cells disrupts autophagy, leading to increased levels of Apolipoprotein E and potentially contributing to disease processes.

## Contribution

This study reveals a novel link between HTT and autophagic regulation of APOE in liver tissue.

## Key findings

- HTT knockout in mouse liver reduces LAMP2A levels, essential for chaperone-mediated autophagy.
- HTT reduction increases APOE levels in liver and cultured cells.
- Loss of HTT function may lead to autophagic cargo accumulation and tissue-specific pathogenesis.

## Abstract

The HTT protein, mutated in Huntington's disease, is expressed throughout the body, and loss of HTT function as an autophagic scaffold may affect tissues and cellular processes. These processes include lipid metabolism potentially regulated upstream by Apolipoprotein E (APOE) and clearance of APOE itself.

To determine the impact of HTT reduction on autophagy and clearance of APOE in cell culture and in mouse liver in vivo.

Western blot analysis was performed on liver tissue from tamoxifen-treated mice with and without UBC-Cre expression, required for tamoxifen-induced HTT knockout (KO). siRNA was used to knockdown (KD) HTT in HepG2 immortalized liver cells.

HTT KO in mouse liver reduces levels of LAMP2A, a protein essential for chaperone-mediated autophagy (CMA) which we previously found is required for optimal degradation of APOE and HTT in cultured cells. In turn, APOE levels were increased with HTT KO in mouse liver, while HTT KD in cell culture decreased levels of APOE.

In the context of liver tissue, reduced CMA may contribute to accumulation of APOE and autophagic cargo resulting from a loss of HTT function in autophagy. The extent to which macroautophagy is upregulated to cope with reduced CMA found with HTT KO may be tissue specific, which may relate to the selectivity of tissue pathogenesis observed in Huntington's disease where loss of normal HTT function may be involved. This study may help elucidate the consequences of systemic HTT reduction on autophagy in liver tissue.