Role of apolipoprotein E in electronegative low-density lipoprotein-induced mitochondrial dysfunction in cardiomyocytes

Chen, Wei-Yu; Chen, Yunfang; Chan, Hua-Cheng; Chung, Ching‐Hu; Peng, Hsien Yu; Ho, Yu-Cheng; Chen, Chu‐Huang; Chang, Kuan‐Cheng; Tang, Chih-Hsin; Lee, An‐Sheng

doi:10.1016/j.metabol.2020.154227

Cited by 13 publications

(26 citation statements)

References 51 publications

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“…Involved in Atherosclerosis from the ER is transferred to the mitochondria [24]. During the development of atherosclerosis, apoE may open the mitochondrial permeability transition pore (MPTP) through the interaction of apoE and VDAC1, thereby playing an important role in mitochondrial dysfunction induced by negatively charged LDL [25]. The secretion of apoE by macrophages occurs through protein kinase A (PKA) and Ca 2+ -dependent pathways along the microtubule network, and its specific expression can prevent atherosclerosis [26].…”

Section: Structural and Functional Proteins Of Mamsmentioning

confidence: 99%

Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

Wang

Luo

2021

Oxidative Medicine and Cellular Longevity

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Atherosclerosis is a chronic lipid-driven inflammatory disease that results in the formation of lipid-rich and immune cell-rich plaques in the arterial wall, which has high morbidity and mortality in the world. The mechanism of atherosclerosis is still unclear now. Potential hypotheses involved in atherosclerosis are chronic inflammation theory, lipid percolation theory, mononuclear-macrophage theory, endothelial cell (EC) injury theory, and smooth muscle cell (SMC) mutation theory. Changes of phospholipids, glucose, critical proteins, etc. on mitochondria-associated endoplasmic reticulum membrane (MAM) can cause the progress of atherosclerosis. This review describes the structural and functional interaction between mitochondria and endoplasmic reticulum (ER) and explains the role of critical molecules in the structure of MAM during atherosclerosis.

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Section: Structural and Functional Proteins Of Mamsmentioning

confidence: 99%

Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

Wang

Luo

2021

Oxidative Medicine and Cellular Longevity

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“…Accumulating evidence suggests that L5 LDL interacts with multiple cells such as endothelial cells [ 8 , 15 , 56 , 57 , 58 ], platelets [ 10 , 11 ], monocytes [ 9 , 59 , 60 , 61 , 62 , 63 ], and cardiomyocytes [ 24 , 64 , 65 , 66 , 67 ]. L5 LDL attracts both monocytes and lymphocytes to endothelial cells (ECs) [ 58 ], indicating the contribution in the early stage of atherosclerosis.…”

Section: Cellular Signaling Of L5 Ldlmentioning

confidence: 99%

“…L5 LDL markers, either percentage or the absolute plasma concentration, can be more reliable than those listed above ( Table 1 ) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 15 , 67 ]. Besides, the molecular mechanisms and the clinical relevance of L5 LDL provide strong evidence-based supports to demonstrate that L5 LDL can be potential biomarkers in the early diagnosis of vascular aging, atherosclerosis and cardiovascular diseases [ 6 , 24 , 25 , 28 , 55 , 56 , 60 , 63 , 70 , 84 ].…”

Section: Implication Of L5 Ldlmentioning

confidence: 99%

“…Besides, L5 LDL has significantly higher levels of apolipoprotein E (apoE) and apolipoprotein AI (apoAI). In cardiomyocytes, apoE interacts with the voltage-dependent anion-selective channel (VDAC), leading to dynamin-related protein 1 (Drp1) phosphorylation and mitochondrial fission [24]. Additionally, apolipoproteins associated with L5 LDL from human plasma particles are found to be highly glycosylated.…”

Section: Glycosylation Of Apolipoproteins In L5 Ldlmentioning

confidence: 99%

“…Alterations in ceramide levels have been recognized in pathological conditions such as Alzheimer's disease [40], type 2 diabetes [41], and cardiovascular diseases [42]. LPC stimulates inflammatory chemokine expression from endothelial cells [43][44][45][46], impairs arterial relaxation [47], increases oxidative stress [48,49] In cardiomyocytes, apoE interacts with the voltage-dependent anion-selective channel (VDAC), leading to dynamin-related protein 1 (Drp1) phosphorylation and mitochondrial fission [24]. Additionally, apolipoproteins associated with L5 LDL from human plasma particles are found to be highly glycosylated.…”

Section: Atherogenic Lipid Moieties Of L5 Ldlmentioning

confidence: 99%

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Clinical Significance of Electronegative Low-Density Lipoprotein Cholesterol in Atherothrombosis

et al. 2020

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Despite the numerous risk factors for atherosclerotic cardiovascular diseases (ASCVD), cumulative evidence shows that electronegative low-density lipoprotein (L5 LDL) cholesterol is a promising biomarker. Its toxicity may contribute to atherothrombotic events. Notably, plasma L5 LDL levels positively correlate with the increasing severity of cardiovascular diseases. In contrast, traditional markers such as LDL-cholesterol and triglyceride are the therapeutic goals in secondary prevention for ASCVD, but that is controversial in primary prevention for patients with low risk. In this review, we point out the clinical significance and pathophysiological mechanisms of L5 LDL, and the clinical applications of L5 LDL levels in ASCVD can be confidently addressed. Based on the previously defined cut-off value by receiver operating characteristic curve, the acceptable physiological range of L5 concentration is proposed to be below 1.7 mg/dL. When L5 LDL level surpass this threshold, clinically relevant ASCVD might be present, and further exams such as carotid intima-media thickness, pulse wave velocity, exercise stress test, or multidetector computed tomography are required. Notably, the ultimate goal of L5 LDL concentration is lower than 1.7 mg/dL. Instead, with L5 LDL greater than 1.7 mg/dL, lipid-lowering treatment may be required, including statin, ezetimibe or PCSK9 inhibitor, regardless of the low-density lipoprotein cholesterol (LDL-C) level. Since L5 LDL could be a promising biomarker, we propose that a high throughput, clinically feasible methodology is urgently required not only for conducting a prospective, large population study but for developing therapeutics strategies to decrease L5 LDL in the blood.

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Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function

Rueter¹,

Rimbach²,

Huebbe³

2022

Cell. Mol. Life Sci.

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Human apolipoprotein E (APOE), originally known for its role in lipid metabolism, is polymorphic with three major allele forms, namely, APOEε2, APOEε3, and APOEε4, leading to three different human APOE isoforms. The ε4 allele is a genetic risk factor for Alzheimer’s disease (AD); therefore, the vast majority of APOE research focuses on its role in AD pathology. However, there is increasing evidence for other functions of APOE through the involvement in other biological processes such as transcriptional regulation, mitochondrial metabolism, immune response, and responsiveness to dietary factors. Therefore, the aim of this review is to provide an overview of the potential novel functions of APOE and their characterization. The detection of APOE in various cell organelles points to previously unrecognized roles in mitochondria and others, although it is actually considered a secretory protein. Furthermore, numerous interactions of APOE with other proteins have been detected, providing indications for new metabolic pathways involving APOE. The present review summarizes the current evidence on APOE beyond its original role in lipid metabolism, to change the perspective and encourage novel approaches to future research on APOE and its isoform-dependent role in the cellular metabolism.

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Role of apolipoprotein E in electronegative low-density lipoprotein-induced mitochondrial dysfunction in cardiomyocytes

Cited by 13 publications

References 51 publications

Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

Clinical Significance of Electronegative Low-Density Lipoprotein Cholesterol in Atherothrombosis

Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function

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