Glucose regulates fatty acid binding protein interaction with lipids and peroxisome proliferator-activated receptor α

Heather A Hostetler,Madhumitha Balanarasimha,Huan Huang,Matthew S Kelzer,Alagammai Kaliappan,Ann B Kier,Friedhelm Schroeder

doi:10.1194/jlr.m005041

Heather A Hostetler, Madhumitha Balanarasimha + Show 5 more

Open Access

https://doi.org/10.1194/jlr.m005041

Copy DOI

Abstract

Although the pathophysiology of diabetes is characterized by elevated levels of glucose and long-chain fatty acids (LCFA), nuclear mechanisms linking glucose and LCFA metabolism are poorly understood. As the liver fatty acid binding protein (L-FABP) shuttles LCFA to the nucleus, where L-FABP directly interacts with peroxisome proliferator-activated receptor-α (PPARα), the effect of glucose on these processes was examined. In vitro studies showed that L-FABP strongly bound glucose and glucose-1-phosphate (K(d) = 103 ± 19 nM and K(d) = 20 ± 3 nM, respectively), resulting in altered L-FABP conformation, increased affinity for lipid ligands, and enhanced interaction with PPARα. In living cells, glucose stimulated cellular uptake and nuclear localization of a nonmetabolizable fluorescent fatty acid analog (BODIPY C-16), particularly in the presence of L-FABP. These data suggest for the first time a direct role of glucose in facilitating L-FABP-mediated uptake and distribution of lipidic ligands to the nucleus for regulation of PPARα transcriptional activity.

Highlights

The pathophysiology of diabetes is characterized by elevated levels of glucose and long-chain fatty acids (LCFA), nuclear mechanisms linking glucose and LCFA metabolism are poorly understood
As the above data showed that glucose increased liver fatty acid binding protein (L-FABP)’s affinity for lipidic ligands (LCFA and LCFA-CoA) and for peroxisome proliferator-activated receptor (PPAR)␣, the possibility that glucose might thereby alter the distribution of LCFA to the nucleus was examined using BODIPY C-16, a fluorescent fatty acid analog that is bound with high affinity by both PPAR␣ [13] and L-FABP [12]
It has been proposed that cytoplasmic lipid binding proteins, such as L-FABP, might function in long-term regulation of hepatic LCFA ␤-oxidation by transporting bound LCFA or LCFA-CoA into the nucleus, directly interacting with nuclear receptors, such as PPAR␣, and transferring these ligands to PPAR␣ for activating transcription of multiple genes involved in LCFA ␤-oxidation

Summary

Introduction

The pathophysiology of diabetes is characterized by elevated levels of glucose and long-chain fatty acids (LCFA), nuclear mechanisms linking glucose and LCFA metabolism are poorly understood. These data suggested that glucose- and glucose metabolite-induced L-FABP structural changes might alter L-FABP’s interaction with phosphate; G-6-P, glucose-6-phosphate; L-FABP, liver fatty acid binding protein.

Results

Conclusion