Pioglitazone Increases Blood-Brain Barrier Expression of Fatty Acid-Binding Protein 5 and Docosahexaenoic Acid Trafficking into the Brain

Yi Ling Low, Liang Jin, Elonie R. Morris, Yijun Pan, Joseph A. Nicolazzo

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Brain levels of docosahexaenoic acid (DHA), an essential cognitively beneficial fatty acid, are reduced in Alzheimer's disease (AD). We have demonstrated in an AD mouse model that this is associated with reduced blood-brain barrier (BBB) transport of DHA and lower expression of the key DHA-trafficking protein, fatty acid-binding protein 5 (FABP5). This study focused on assessing the impact of activating peroxisome proliferator-activated receptor (PPAR) isoforms on FABP5 expression and function at the BBB. Using immortalized human brain endothelial (hCMEC/D3) cells, a 72 h treatment with the PPARα agonist clofibrate (100 μM), and PPARβ/δagonists GW0742 (1 μM) and GW501506 (0.5 μM), did not affect FABP5 protein expression. In contrast, the PPARγagonists rosiglitazone (5 μM), pioglitazone (25 μM), and troglitazone (1 μM) increased FABP5 protein expression by 1.15-, 1.18-, and 1.24-fold in hCMEC/D3 cells, respectively, with rosiglitazone and pioglitazone also increasing mRNA expression of FABP5. In line with an increase in FABP5 expression, pioglitazone increased 14C-DHA uptake into hCMEC/D3 cells 1.20- to 1.33-fold over a 2 min period, and this was not associated with increased expression of membrane transporters involved in DHA uptake. Furthermore, treating male C57BL/6J mice with pioglitazone (40 mg/kg/day for 7 days) led to a 1.79-fold increase in BBB transport of 14C-DHA over 1 min, using an in situ transcardiac perfusion technique, which was associated with a 1.82-fold increase in brain microvascular FABP5 protein expression. Overall, this study demonstrated that PPARγcan regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.

Original languageEnglish
Pages (from-to)873-884
Number of pages12
JournalMolecular Pharmaceutics
Volume17
Issue number3
DOIs
Publication statusPublished - 2 Mar 2020

Keywords

  • Alzheimer's disease
  • blood-brain barrier
  • fatty acid-binding protein 5
  • peroxisome proliferator-activated receptor
  • pioglitazone

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