Whole body cholesterol metabolism is impaired in Huntington's disease

We previously reported impaired cholesterol biosynthesis in rodent Huntington Disease (HD) models and HD patients’ fibroblasts and post mortem brains. We also found that plasma levels of 24S-hydroxycholesterol (24OHC), the brain specific elimination product of cholesterol considered a marker of brain cholesterol turnover, were significantly reduced in HD patients at any disease stage. In the present study we analysed by mass spectrometry the fasting plasma levels of cholesterol, its biosynthetic precursors lanosterol and lathosterol, of the whole-body elimination products 27-hydroxycholesterol and of brain 24OHC in a cohort of premanifest and HD patients at different disease stages. We found that the cholesterol precursors lanosterol and lathosterol (both index of whole body cholesterol synthesis), the levels of the bile acid precursor 27-hydroxycholesterol, and of the brain specific 24OHC, were all significantly reduced in manifest HD patients, suggesting that whole-body and brain cholesterol homeostasis are both impaired in HD.

► Impaired cholesterol biosynthesis in rodent models of Huntington Disease (HD). ► Reduced brain cholesterol turnover in HD patients as plasma 24S-hydroxycholesterol. ► Markers of cholesterol whole body synthesis reduced in HD patients. ► Cholesterol whole body and cerebral elimination reduced in HD patients. ► Reduced cerebral and whole body cholesterol metabolism in HD patients.