Altered cholesterol and fatty acid metabolism in Huntington disease

Division of Epidemiology, Department of Community and Preventive Medicine and Preventive Cardiology Unit, Box 644, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14620, USA.
Journal of Clinical Lipidology (Impact Factor: 3.9). 02/2010; 4(1):17-23. DOI: 10.1016/j.jacl.2009.11.003
Source: PubMed


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.

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Available from: Tom Brenna, Apr 24, 2015
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    • "HD is linked directly with a form of dysglycemia leading to a catabolic state characterized by weight loss and a lower body mass index than the healthy population. The lipid dysregulation involves high levels of triglycerides and LDL, which also creates a risk of microvascular and macrovascular pathologies on the long (124, 125). Insulin resistance is therefore thought to be one of the main factors of the pathogenesis of HD leading to severe neurobiological impairments. "
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    ABSTRACT: With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington' disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand-receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum.
    Frontiers in Endocrinology 09/2014; 5:142. DOI:10.3389/fendo.2014.00142
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    • "Cholesterol fulfills both functional and structural tasks, since it regulates the cell membrane fluidity and stability (Ohvo-Rekila et al., 2002) and constitutes the precursor of bile acids and steroid hormones including vitamin D (Repa and Mangelsdorf, 2000). Although we reached a great knowledge about the patho-physiological roles of cholesterol metabolism perturbation in several organs and tissues, only little information is available on the regulation of cholesterol homeostasis in the central nervous system (CNS) where this lipid is involved in the maintenance of several neuronal functions such as the conduction of the action potential, the stabilization of synapses, and the formation of lipid rafts (Block et al., 2010). Even though the human brain accounts for the 2% of the total body weight, it has been established that approximately 25% of the total content of cholesterol present in humans is found in the CNS (Bjorkhem and Meaney, 2004; Dietschy and Turley, 2004). "
    Dataset: 2013 JCP

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    • "Changes in metabolism in experimental models of HD have recently gained significant attention [24], [52], [53], [77], [78]. Despite a sometimes severe weight loss at late stages of the disease, HD patients have been described to display increased appetite [79], [80], insulin resistance, alteration in leptin levels and higher susceptibility to develop diabetes [10], [12], [81], [82]. Metabolic dysfunction with obesity and insulin as well as leptin resistance can be observed in genetic models of HD expressing human full-length htt, such as the YAC and BACHD mice [24], [26], [83]. "
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    ABSTRACT: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of autophagy.
    PLoS ONE 12/2013; 8(12):e83050. DOI:10.1371/journal.pone.0083050 · 3.23 Impact Factor
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