Lipid chaperones and metabolic inflammation

Abstract

Over the past decade, a large body of evidence has emerged demonstrating an integration of metabolic and immune response pathways. It is now clear that obesity and associated disorders such as insulin resistance and type 2 diabetes are associated with a metabolically driven, low-grade, chronic inflammatory state, referred to as "metaflammation." Several inflammatory cytokines as well as lipids and metabolic stress pathways can activate metaflammation, which targets metabolically critical organs and tissues including adipocytes and macrophages to adversely affect systemic homeostasis. On the other hand, inside the cell, fatty acid-binding proteins (FABPs), a family of lipid chaperones, as well as endoplasmic reticulum (ER) stress, and reactive oxygen species derived from mitochondria play significant roles in promotion of metabolically triggered inflammation. Here, we discuss the molecular and cellular basis of the roles of FABPs, especially FABP4 and FABP5, in metaflammation and related diseases including obesity, diabetes, and atherosclerosis.

Figure 1

Interaction of adipocytes and macrophages. FABPs, FABP4, and FABP5, in adipocytes and macrophages, are critical for regulating inflammatory and metabolic responses in each type of cells and also interaction of the two types of cells.

Figure 2

FABP4 bound with a fatty acid or a small molecule inhibitor. (a) Human FABP4 binds to an endogenous fatty acid, palmitic acid, as a twisted U-shaped entity in the binding pocket (PDB code: 2hnx). (b) Human FABP4 crystallized in complex with BMS309403, a synthetic FABP4 inhibitor, is shown (PDB code: 2nnq). The molecule occupies the internal binding pocket of FABP4 and competitively inhibits binding of endogenous fatty acids. The figures were created using PyMOL.