Altered cholesterol and fatty acid metabolism in Huntington disease

Abstract

Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

Keywords: Huntington disease; cholesterol; insulin resistance; omega-3 fatty acids; triglycerides.

Fig. 1

The cholesterol and triglyceride-phospholipid biosynthesis pathways. The genes in green were found to be decreased in the inducible Huntington disease cell model by microarray analysis; the genes in blue were not present on the microarray filters. All of the genes bearing an SRE in their promoter, and regulated by sterol regulatory element binding proteins (SREBP), are tagged with a red asterisk. Sterol C14-reductase, sterol C4-methyl oxidase, NAD(P)H steroid dehydrogenase, 17β-hydroxysteroid dehydrogenase-7, 3β-hydroxysteroid-Δ-Δ-isomerase, sterol C-5-desaturase and desmosterol reductase, localized between Cyp51 and 7DHCRed, are likely also SREBP-dependent genes. The triglyceride-phospholipid biosynthetic pathway has not yet been carefully analysed in Huntington disease but, based on the findings from Sipione et al. herein summarized, it may well be affected. From