Effect of Sublethal Copper Overload on Cholesterol <i>De Novo</i> Synthesis in Undifferentiated Neuronal Cells

Zubillaga, Marlene; Rosa, Diana Esther; Astiz, Mariana; Tricerri, M. Alejandra; Arnal, Nathalie

doi:10.1021/acsomega.2c00703

Cited by 5 publications

(16 citation statements)

References 82 publications

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“…Moreover, Aβ not only increases the ABCA1 protein level and significantly reduces cholesterol efflux but also directly affects HMGCR activity and the production of cholesterol in nerve cells. Zubillaga M et al [ 87 ] obtained the same results in another neuronal cell line, i.e., the neuroblastoma cell line (SH-SY5Y). According to their studies, activating HMGCR, increasing ROS, and promoting Chol synthesis may promote APP redistribution in rafts, which contribute to amyloid processing of the protein, and then increase the level of Aβ.…”

Section: Hmgcr-mediated Neuroinflammationmentioning

confidence: 56%

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Zhou,

Wu,

Wang

et al. 2023

IJMS

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Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.

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Section: Hmgcr-mediated Neuroinflammationmentioning

confidence: 56%

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Zhou,

Wu,

Wang

et al. 2023

IJMS

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“…The fact that more Cho was synthesized after Cu + NAC treatment, while we observed no increases in ROS compared to the control, suggests that this metal may be directly influencing Cho synthesis, in addition to its role in ROS generation. In line with this, we recently demonstrated in vitro that Cu, unlike iron or zinc, may promote de novo Cho synthesis in a ROS-independent manner [ 16 ].…”

Section: Discussionmentioning

confidence: 68%

“…It has been observed that individuals with AD exhibit elevated levels of Cu in plasma [ 9 , 38 ]. In this context, we recently showed that a sublethal concentration of Cu can induce Cho de novo synthesis in immature neurons [ 16 ]. Given that astrocytes play a pivotal role in the synthesis and supply of Cho to neurons within the mature brain, our objective was to investigate the potential sex-dependent effects of sublethal Cu concentrations on Cho metabolism in primary astrocyte cultures.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the use of Cu-based pesticides and Cu intrauterine devices may also be a cause of Cu overload in humans [ 12 , 13 ]. Excess Cu not only increases oxidative stress through the Harber-Weiss or Fenton reactions by modifying molecular oxygen leading to the production of ROS [ 14 , 15 ] but also contributes to Cho de novo synthesis, both in a manner influenced by reactive oxygen species (ROS) and independently of ROS [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes

Zubillaga,

Tau,

Rosa

et al. 2024

Biol Sex Differ

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Background Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer’s disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis. Methods We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts. Results Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males. Conclusions Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.

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“…[ 32 ] Cu can also regulate cholesterol homeostasis in a reactive oxygen species (ROS)-dependent manner. [ 33 ] Although the mechanism of Cu in the formation of gallstones remains unclear, more attention should be paid to Cu deficiency and the prevalence of GSD.…”

Section: Discussionmentioning

confidence: 99%

The association between intakes of dietary trace minerals and gallstone disease: A cross-sectional study from National Health and Nutrition Examination Survey 2017 to 2018

Yan,

Yu,

Fang

et al. 2024

Medicine

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The gallstone disease is becoming increasingly prevalent worldwide. Dietary trace minerals have been proven to be closely related to many metabolic diseases, and this study aims to explore the association between intakes of dietary trace minerals (copper, iron, selenium, and zinc) and gallstone disease (GSD). Using the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, intakes of dietary trace minerals and GSD data were obtained through a 24-hour recall and diagnostic questionnaire, respectively. Weighted logistic regression models were used to identify the association between intakes of dietary trace minerals and the prevalence of GSD, and the results were presented as odds ratios (OR) and 95% confidence intervals (95% CI). A total of 4077 participants were included in the final analysis, of which 456 participants had GSD and 3621 participants serving as the control group. No significant associations between GSD and intakes of dietary trace minerals (iron, selenium, and zinc) were found. However, after adjusting for all covariates, significant association was demonstrated between dietary copper (Cu) intake and GSD (OR = 0.66, 95% CI = 0.45–0.98). After conducting a weighted quantile logistic regression, a significant negative correlation was also found between dietary Cu intake and highest GSD quartile (Q4) (OR = 0.45, 95% CI = 0.26–0.80). Following the research outlined above, no association was found between intakes of dietary trace minerals (iron, selenium, and zinc) and GSD; however, a linear negative association was identified between dietary Cu intake and GSD.

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Effect of Sublethal Copper Overload on Cholesterol De Novo Synthesis in Undifferentiated Neuronal Cells

Cited by 5 publications

References 82 publications

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes

The association between intakes of dietary trace minerals and gallstone disease: A cross-sectional study from National Health and Nutrition Examination Survey 2017 to 2018

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