Abstract
Reversible redox modification of cysteine thiols is crucial for protecting proteins from irreversible detrimental change. However, the physiological significance of the redox modification of apolipoprotein (apo) E is unclear. Here, we hypothesized that the disulfide-linked complexes of apoE3 corresponding to the representative reversible-modified apoE3 play a protective role against oxidative stress. The effects of disulfide bond formation on oxidative stress on apoE3 were evaluated with a band-shift assay. Maleimide-labeled apoE3 and unlabeled apoE3 were defined as the reduced (r)-apoE3 and non-reduced (nr)-apoE3 forms, respectively. Hydrogen peroxide-induced oxidation decreased for reduced-form apoE (r-apoE3) but increased for nr-apoE3. Induction of apoE3-AII complex formation with excess of apoAII markedly suppressed the oxidative stress-induced increase in nr-apoE3 (P<0.001) and enhanced homodimer formation. The apoE3-AII complex was more dominant in high-density lipoprotein (HDL) than in very low-density lipoprotein. Under oxidative stress, HDL showed a significant decrease, rather than an increase, in nr-apoE3 levels with a concomitant significant increase in apoE3-AII levels (P<0.005). This finding suggests that the majority of nr-apoE3 in HDL exists in a reversible oxidized form. The apoE3-AII complex, formed from the reversible oxidized apoE3, is beneficial for maintaining the redox equilibrium of apoE3 by preventing the modification of apoE3 to its irreversible oxidized form. The apoE3-AII complex may be possibly implicated in the pathophysiology of various apoE-related diseases.
Highlights
Apolipoprotein E, a 35-kDa glycoprotein comprising 299 amino acids residues, is primarily synthesized in the liver and plays a pivotal role in lipid transport and metabolism [1]
The redox profiles of apoE3 in very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) isolated from the sera of three healthy volunteers with apoE3/E3 phenotype were determined by the band-shift assay using polyethylene glycol (PEG)-PC-Mal
As per our previous findings [17], naive VLDL and HDL showed differences in the redox status of apoE3; i.e., r-apoE3 was more dominant in VLDL than in HDL (P
Summary
Apolipoprotein E (apoE), a 35-kDa glycoprotein comprising 299 amino acids residues, is primarily synthesized in the liver and plays a pivotal role in lipid transport and metabolism [1]. It is expressed in the brain and is involved in cerebral lipid metabolism, and in the growth and repair of the central nervous system [2]. ApoE has been shown to play a role in the development of various diseases [3]. ApoE4 is a major causative factor of sporadic late-onset Alzheimer’s disease (AD) and its frequency is markedly increased in AD [4]. The actual role of apoE4 in the development of AD is yet unclear, the knowledge of the pathological alterations in other isoforms during AD development may lead to a promising breakthrough in AD pathology
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