Hyperhomocysteinemia ja B-vitamiinijoukko

https://www.ncbi.nlm.nih.gov/pubmed/27929536# Abstract

Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect.
Moreover, HHcy increased unfolded protein response (UPR).

  Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy.

 Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro.

 Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.

PMID:

27929536

PMCID:

PMC5260994

DOI:

10.1038/cddis.2016.374

[Indexed for MEDLINE]

Free PMC Article

Hyperhomocysteinemia (HHcy) is a clinical condition characterized by increased levels of total plasma homocysteine (Hcy) and carries an increased risk for stroke.¹ 

 Hcy is a methionine precursor and a sulphur amino acid intermediate in the (re)methylation and trans-sulfuration pathways.

  There are three major dietary cofactors in Hcy metabolism: Vitamin B₆, B₁₂, and folate. Deficiencies in these vitamins were more prevalent in the developing countries and may account for the increased incidence of HHcy and stroke found in those countries.²

  Additionally, decreased folate, Vitamin B₆, and Vitamin B₁₂ plasma levels were associated with HHcy;³ 

moreover, Vitamin B therapy reduced both Hcy levels and stroke risk.^{4, 5} 

HHcy is frequently categorized into three categories:

 moderate (plasma Hcy concentrations of 15–30 μmol/l), 

intermediate (plasma Hcy concentrations of 31–100 μmol/l),

and severe (plasma Hcy concentrations 100 μmol/l).⁶