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Pettegrew, Jay W.; Panchalingam, K.; Hamilton, Ronald L.; McClure, Richard J.

doi:10.1023/a:1011603916962

Cited by 262 publications

(113 citation statements)

References 70 publications

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“…For example, the total phospholipid and sulfatide content in AD brains was decreased compared to that in controls (Skinner et al, 1989; Soderberg et al, 1992; Gottfries et al, 1996; Pettegrew et al, 2001; Han et al, 2002; Cheng et al, 2003). On the other hand, ceramide, a pro-apoptotic lipid was found to be elevated in the brains (Cutler et al, 2004) and CSF of patients with AD (Satoi et al, 2005).…”

Section: Lipid Dyshomeostasis In Neurodegenerative Diseasesmentioning

confidence: 99%

HFE gene variants, iron, and lipids: a novel connection in Alzheimerâ€™s disease

2014

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Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer’s disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.

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Section: Lipid Dyshomeostasis In Neurodegenerative Diseasesmentioning

confidence: 99%

HFE gene variants, iron, and lipids: a novel connection in Alzheimerâ€™s disease

2014

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“…In addition to plaques and tangles, AD is associated with an array of biochemical alterations, including perturbations in cholesterol homeostasis 2, 3, phospholipid metabolism 4, calcium trafficking 5, and mitochondrial function 6. Notably, these functions share a common feature in that they are associated with a subcompartment of the endoplasmic reticulum (ER) known as mitochondria‐associated ER membranes (MAM).…”

Section: Introductionmentioning

confidence: 99%

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

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“…These monounsaturated fatty acids are used as substrates for the synthesis of triglycerides, wax esters, cholesteryl esters, and membrane phospholipids (2)(3)(4). The saturated to monounsaturated fatty acid ratio affects membrane phospholipid composition, and alteration in this ratio has been implicated in a variety of disease states, including diabetes, obesity, cardiovascular disease, neurological disease, skin disorders, and cancer (5)(6)(7)(8)(9)(10). For this reason, the expression of SCD is of physiological importance in normal and disease states.…”

mentioning

confidence: 99%

Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle

Rahman

Dobrzyń

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

171

149

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We have shown previously that mice with a targeted disruption in the stearoyl-CoA desaturase 1 gene (SCD1 ؊/؊ ) have increased insulin sensitivity compared with control mice. Here we show that the SCD1 ؊͞؊ mice have increased insulin signaling in muscle. The basal tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2 are elevated. The tyrosine phosphorylation of insulin-like growth factor-1 receptor was similar between SCD1 ؉͞؉ and SCD1 ؊͞؊ mice. The association of insulin receptor substrates 1 and 2 with ␣p85 subunit of phosphatidylinositol 3-kinase as well as the phosphorylation of Akt-Ser-473 and Akt-Thr-308 are also elevated in the SCD1 ؊͞؊ mice. Interestingly, the mRNA levels, protein mass, and activity of the protein-tyrosine phosphatase-1B implicated in the attenuation of the insulin signal are reduced in the SCD1 ؊͞؊ mice, whereas the levels of the leukocyte antigen-related protein phosphatase are similar between two groups of mice. The content of glucose transporter 4 in the plasma membrane and basal as well as insulin-mediated glucose uptake are increased in the SCD1 ؊͞؊ mice. In addition, the muscle glycogen content and the activities of glycogen synthase and phosphorylase are increased in the SCD1 ؊͞؊ mice. We hypothesize that loss of SCD1 function induces increased insulin signaling at least in part by a reduction in the expression of protein-tyrosine phosphatase 1B. SCD1 could be a therapeutic target in the treatment of diabetes.

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Untitled

Cited by 262 publications

References 70 publications

HFE gene variants, iron, and lipids: a novel connection in Alzheimerâ€™s disease

HFE gene variants, iron, and lipids: a novel connection in Alzheimerâ€™s disease

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle

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