GRP78 Activity Moderation as a Therapeutic Treatment against Obesity

Abstract

Glucose-regulated protein 78 (GRP78), a molecular chaperone, is overexpressed in patients suffering from obesity, fatty liver, hyperlipidemia and diabetes. GRP78, therefore, can be not only a biomarker to predict the progression and prognosis of obesity and metabolic diseases but also a potential therapeutic target for anti-obesity treatment. In this paper, GRP78 inhibitors targeting its ATPase domain have been reviewed. Small molecules and proteins that directly bind GRP78 have been described. Putative mechanisms of GRP78 in regulating lipid metabolism were also summarized so as to investigate the role of GRP78 in obesity and other related diseases and provide a theoretical basis for the development and design of anti-obesity drugs targeting GRP78.

Keywords: GRP78; action mechanism; metabolic disorder; molecular target; obese.

Figure 2

Ingenuity Pathway Analysis (IPA) result of GRP78 (HSPA5) with its interacting proteins relevant to obesity. Using “obesity” as the keyword, 1216 proteins, including HSPA5 (GRP78), were obtained from the IPA database. According to the analysis of the “Build-Path Explorer” module, 139 molecules have interactions with HSPA5.

Figure 3

GRP78 inhibitors targeting its ATPase/nucleotide-binding domain.

Figure 1

Anti-obesity role of GRP78 and downstream molecular functions associated with obesity. Roles and downstream pathways of GRP78 relevant to obesity initiated by binding of α2-macroglobulin-GRP78 that triggers the expression of IP₃, RAS and MAPK, PAk2, PI3K, PLD, COX2, and cPLA2 and increases concentrations of cAMP, Ca²⁺ and pH value (left), which can activate the downstream pathways (right). Green arrows indicate up-expression. AMPK, adenosine monophosphate (AMP) activated protein kinase; Akt, an ubiquitous serine/threonine kinase, also known as protein kinase B (PKB) or RAS-alpha; ATF2, activating transcription factor-2; cAMP, cyclic adenosine monophosphate; C/EBPα, CCAAT/enhancer-binding protein α (which CCAAT is a distinct pattern of nucleotides with GGCCAATCT consensus sequence that occurs upstream by 60–100 bases to the initial transcription site); COX₂, cicloxigenases; cPLA2, cytosolic phospholipase A 2; ERS, endoplasmic reticulum stress; GLUT4, glucose transporter type 4; GRP78, 78 kDa glucose-regulated protein; HSP70, heat shock protein 70 family; HSL, hormone sensitive lipase; HSPA12A, heat shock protein family a (hsp70) member 12A; IP3, inositol triphosphate; IR, insulin resistance; mTOR, mammalian target of rapamycin; PAk2, p21-activated protein kinase; PGC1α, PPARγ coactivator 1α; PDK1, pyruvate dehydrogenase kinase 1; PLD, phospholipase D; PI3K, phosphoinositide 3-kinases; PPARγ, peroxisome proliferator activated receptor γ; PLIN, perilipin; p38 MAPK, p38 mitogen-activated protein kinases; p-Akt, phosphorylated Akt; RAS, renin-angiotensin system; RTN3, reticular protein 3; SIRT1, sirtuin1; SREBP-1c, sterol regulatory element binding protein-1c; SREBPs, sterol regulatory element binding protein; SCAP, SREBP cleavage-activating protein; TG, triglyceride fatty acid; UCP1, uncoupling protein 1.

Figure 4

Regulatory functions of GRP78 and downstream molecular functions relevant to anti-obesity. Domain structures (top) and 3D structural model (middle) of GRP78, molecules interacting with either the ATPase domain (in magenta), β sandwich subdomain (in red) or the helix subdomain (in cyan) of GRP78, and chemical structures of nucleosides (bottom). The cited small molecules can up (+) or down (−) regulate GRP78. Modified from [72].