Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases

Song, Yuelin; Liu, Junjun; Zhao, Kang; Gao, Ling; Zhao, Jiajun

doi:10.1016/j.cmet.2021.09.001

Cited by 145 publications

(115 citation statements)

References 155 publications

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“…Early recognition of the discordant/concordant LDL-C and RC can help distinguish high-risk patients who are predisposed to DM. As TRLs are cholesterol-rich, RC has attracted attention for its pathogenic capability due to a recently proposed concept-that of cholesterol toxicity-and this has engendered novel perspectives on the development of DM [34]. Previous cohort studies of the general population and coronary artery disease patients suggested that RC was a predictor of new-onset hyperglycemia, superior to other traditional lipid parameters [17,18,35].…”

Section: Discussionmentioning

confidence: 99%

“…However, cholesterol-lowering strategies benefit pancreatic β-cell function [38][39][40][41]. Excess cholesterol is also able to induce endoplasmic reticulum stress and mitochondrial dysfunction and promote reactive oxygen species (ROS) production in pancreatic β-cells, ultimately leading to structural changes in insulin-containing granules [34]. RC is more abundant, larger, and carries more cholesterol than LDL-C particles; hence, it can be inferred that RC is more harmful to pancreatic β-cells [8].…”

Section: Rcmentioning

confidence: 99%

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The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus

Liu

Guo

et al. 2022

Cardiovasc Diabetol

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Background Previous research has linked elevated low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) with diabetes mellitus (DM). The present study aims to estimate the RC-related DM risk beyond LDL-C, and to investigate the extent to which the association of RC and DM is mediated via insulin resistance and inflammation. Methods We enrolled 7308 individuals without previous history of DM into the present study from the China Health and Nutrition Survey. Fasting RC was calculated as total cholesterol minus LDL-C and high-density lipoprotein cholesterol. Subjects were divided into four groups according to their LDL-C (100 mg/dL) and RC (24 mg/dL) levels to evaluate the role of LDL-C vs. RC on DM. A logistic regression analysis was then employed to evaluate the relationships between the discordant/concordant LDL-C and RC and DM. A mediation analysis was undertaken to identify potential mediators. Results Of all the participants, a total of 625 (8.55%) patients were newly diagnosed with DM. Compared to the high LDL-C/low RC group, the low LDL-C/high RC group was more common in DM patients. After a multivariate adjustment, elevated LDL-C and RC were associated with DM. Moreover, the low LDL-C/high RC group and the high LDL-C/low RC group manifested a 4.04-fold (95% CI 2.93–5.56) and 1.61-fold (95% CI 1.21–2.15) higher risk of DM, relative to those with low LDL-C/low RC. The subgroup analysis indicated that low LDL-C/high RC was more likely to be related to DM in females. Similar results were also shown when the sensitivity analyses were performed with different clinical cut-points of LDL-C. Insulin resistance and inflammation partially mediated the association between RC and DM. Conclusions Our findings provided evidence for RC beyond the LDL-C associations with DM that may be mediated via insulin resistance and the pro-inflammatory state. In addition, women are more susceptible to RC exposure-related DM.

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Section: Discussionmentioning

confidence: 99%

Section: Rcmentioning

confidence: 99%

The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus

Liu

Guo

et al. 2022

Cardiovasc Diabetol

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“…Considering these reports, it is conceivable that women in group 1, who were prone to increases in serum cholesterol levels, may be more susceptible to oxidative stress, with lower QOL scores related to the psychological parameters, than group 2 women. In addition, excess cholesterol plays a role in the pathogenesis of chronic non-communicable diseases (CNCDs), such as atherosclerosis, diabetes, chronic kidney disease, hepatic disease, Alzheimer's disease, osteoporosis, and osteoarthritis, at least in part, via mitochondrial dysfunction-induced reactive oxygen species [37]. Such CNCDs and their risk factors may also exert an impact on QOL [38].…”

Section: Discussionmentioning

confidence: 99%

“…One possible reason for us being unable to observe an interaction between the four SNPs and changes in the SF-36 scores in men may be the small sample size; the number of male participants (n = 31) was approximately 50% of that of the female participants (n = 61) in the study. Another reason for the women-specific beneficial effects of CoQ 10 supplementation may stem from reduced estrogen level changes associated with menopause, leading to a high risk of excess serum cholesterol accumulation, resulting in CNCDs, such as cardiovascular disease [37,40,41]. Serum cholesterol levels plateau in men >50 years of age [41].…”

Section: Discussionmentioning

confidence: 99%

CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Associated with Coenzyme Q10 Availability Affect the Subjective Quality of Life Score (SF-36) after Long-Term CoQ10 Supplementation in Women

et al. 2022

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The single nucleotide polymorphisms (SNPs) rs3808607, rs2072183, rs2032582, and rs1761667 are associated with coenzyme Q10 (CoQ10) bioavailability in women after long-term CoQ10 supplementation. However, the beneficial aspects of the association between these SNPs and CoQ10 supplementation remain unknown. We investigated their relationship using the subjective quality of life score SF-36 by reanalyzing previous data from 92 study participants who were receiving ubiquinol (a reduced form of CoQ10) supplementation for 1 year. Two-way repeated-measures analysis of variance revealed a significant interaction between rs1761667 and the SF-36 scores of role physical (p = 0.016) and mental health (p = 0.017) in women. Subgrouping of participants based on the above four SNPs revealed significant interactions between these SNPs and the SF-36 scores of general health (p = 0.045), role emotional (p = 0.008), and mental health (p = 0.019) and increased serum CoQ10 levels (p = 0.008), suggesting that the benefits of CoQ10 supplementation, especially in terms of psychological parameters, are genotype-dependent in women. However, significant interactions were not observed in men. Therefore, inclusion of SNP subgrouping information in clinical trials of CoQ10 supplementation may provide conclusive evidence supporting other beneficial health effects exerted by the association between these SNPs and CoQ10 on women.

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“…Complications of atherosclerosis, ischemic heart disease and stroke, are among the leading causes of death [4]. In addition to atherosclerosis, excess cholesterol may also be involved in the pathogenesis of other diseases, such as non-alcoholic fatty liver disease and diabetes [5].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

Karpale

Hukkanen

Hakkola

2022

Cells

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Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.

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Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases

Cited by 145 publications

References 155 publications

The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus

The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus

CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Associated with Coenzyme Q10 Availability Affect the Subjective Quality of Life Score (SF-36) after Long-Term CoQ10 Supplementation in Women

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

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