Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the huntingtin gene. Neurodegeneration of striatum and cortex with a severe atrophy at MRI are common findings in HD. The expression of genes involved in the cholesterol biosynthetic pathway such as HMG-CoA reductase and the levels of cholesterol, lanosterol, lathosterol and 24S-hydroxycholesterol are reduced in the brain, striatum and cortex in several HD mouse models. Mutant huntingtin affects the maturation and translocation of SREBP and cannot up-regulate LXR. There is a lower synthesis and transport of cholesterol from astrocytes to neurons via ApoE. In primary oligodendrocytes, mutant huntingtin inhibits the regulatory effect of PGC1 alpha on cholesterol metabolism and the expression of Myelin Basic Protein. In humans the decrease of plasma 24S-hydroxycholesterol follows disease progression proportionally to motor and neuropsychiatric dysfunctions and MRI brain atrophy. Huntingtin seems to play a regulatory role in lipid metabolism. Dysregulation of PGC1 alpha and mitochondrial dysfunction may reduce synthesis of Acetyl-CoA and ATP contributing to the cerebral and whole body impairment of cholesterol metabolism. (C) 2014 Elsevier Inc. All rights reserved.