Elsevier

Journal of Clinical Lipidology

Volume 4, Issue 1, January–February 2010, Pages 17-23
Journal of Clinical Lipidology

Review Article
Altered cholesterol and fatty acid metabolism in Huntington disease

https://doi.org/10.1016/j.jacl.2009.11.003Get rights and content

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 that result 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.

Section snippets

Lipid metabolism in Huntington disease

Cholesterol is crucial for myelin membrane growth, and mice that cannot properly synthesize cholesterol manifest tremor and ataxia.5 In addition to its central nervous system-specific role, cholesterol is an essential component of all cell membranes, acting as a structural component, organizing signal transduction in the lipid rafts of cell membranes, and playing a role in synaptogenesis and in neurotransmitter release within synapses.6 Cholesterol also plays a vital role as a cofactor for

Insulin resistance in Huntington disease

Insulin resistance is a pathophysiologic state associated with obesity and aging and characterized by hyperglycemia and dysfunctional lipid metabolism.17 It is associated with an increased risk of cardiovascular disease and diabetes mellitus as well as certain neoplasms including those of the breast and colon. The lipid disorder tends to consist of high triglycerides and small, dense low-density lipoprotein, with an accompanying high number of atherogenic (apoB) particles. The primary concerns

The role of omega-3 fatty acids in central nervous system health

The state of insulin resistance is characterized by hyperglycemia, abnormal lipoprotein metabolism, and elevated levels of circulating free fatty acids.17 The intake and concentrations of long-chain polyunsaturated fatty acids, including the fish-derived omega-3 fatty acids docosahexaenoic (DHA) and eicosapentaenoic acids (EPA), are negatively correlated with insulin resistance and its manifestations, whereas intake and concentrations of saturated fatty acids are positively correlated.23 A

Implications of disturbed lipid metabolism in Huntington disease

EPA's potential neuroprotective effects and the disrupted fatty acid metabolism in Huntington disease raise the question of whether targeting lipid metabolism may be useful therapies for individuals with Huntington disease. The fact that EPA has beneficial effects on triglycerides is not novel. However, because Huntington disease is characterized by insulin resistance and hypertriglyceridemia is one characteristic of insulin resistance, a beneficial effect of EPA on triglycerides in Huntington

Future directions for the treatment of Huntington disease

Because Huntington disease is characterized by a pattern of impaired insulin secretion and insulin resistance in the setting of hypercatabolism and weight loss, the presentation of insulin resistance and diabetes appears to be very different than that for the majority of individuals with type 2 diabetes mellitus and the metabolic syndrome. Reductions in insulin secretion suggest a pathophysiology similar to type 1 diabetes mellitus, but this form of diabetes is immunologic, not degenerative, in

Financial disclosures

The project was supported by grant number KL2 RR 024136 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research, and RO1 HG 02449 from the National Human Genome Research Institute, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering

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