Expression and Function of Zinc-α2-Glycoprotein

Abstract

Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.

Keywords: Glucose; Insulin sensitivity; Lipid; Metabolism; Neuron; Zinc-α2-glycoprotein.

Fig. 1

The known molecular mechanisms by which zinc-α2-glycoprotein (ZAG) participates in lipid metabolism. Molecules colored in green are known to be upregulated by ZAG directly or indirectly, and those colored in grey are known to be downregulated by ZAG directly or indirectly. The molecule colored in yellow (PPARγ) is affected by ZAG but the results are controversial. Blue arrows indicate promotional effects, red arrow indicates inhibitory effects, and yellow arrow indicates controversial effects. ACC, acetyl-CoA carboxylase; ATGL, adipose triglyceride lipase; C/EBPα, CAAT-enhancer-binding proteins α; CIDEA, cell death-inducing DNA fragmentation factor alpha-like effector A; CPT1A, carnitine palmitoyltransferase 1A; DGAT, acyl-coenzyme A: diacylglycerol transferase; EBF2, early B cell factor 2; FAS, fatty-acid synthase; HSL, hormone-sensitive lipase; MAPK, mitogen-activated protein kinase; mtTFA, mitochondrial transcription factor A; NRF-1/2, nuclear respiratory factor-1/2; PGC1α, PPARγ coactivator 1α; PKA, protein kinase A; PPARγ, peroxisome proliferator-activated receptor γ; Prdm16, PR/SET domain 16; UCP, uncoupling protein.

Fig. 2

The known molecular mechanisms by which zinc-α2-glycoprotein (ZAG) participates in glucose metabolism. Descriptions of molecules and arrows in different colors are as in Fig. 1. cAMP, cyclic adenosine monophosphate; GLUT4, glucose transporter 4; IRS, insulin receptor substrate; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α.

Fig. 3

Molecular mechanisms underlying the regulation of insulin sensitivity by zinc-α2-glycoprotein (ZAG). Descriptions of molecules and arrows in different colors are as in Fig. 1. GLUT4, glucose transporter 4; IRS, insulin receptor substrate; PP2A, protein phosphatase 2A; PPARγ, peroxisome proliferator-activated receptor γ; SGLT2, sodium-dependent glucose transporter 2.

Fig. 4

The molecular mechanisms associated with zinc-α2-glycoprotein (ZAG). Descriptions of molecules and arrows in different colors are as in Fig. 1. CD, cluster of differentiation; ERK, extracellular regulated protein kinases; FAS, fatty acid synthase; IL, interleukin; MCP-1, monocyte chemoattracctant protein; mTOR, mammalian target of rapamycin; PTEN, phosphate and tension homology deleted on chromsome ten; RANTES, regulated upon activation, normal T cell expressed and presumably secreted protein; TGFβ, tumor growth factor β; TH, thyroid hormone; TNFα, tumor necrosis factor α.

Fig. 5

Possible molecular mechanisms by which zinc-α2-glycoprotein (ZAG) participates in epilepsy. Descriptions of molecules and arrows in different colors are as in Fig. 1. ERK, extracellular regulated protein kinases; GABA, γ-aminobutyric acid; IL, interleukin; mTOR, mammalian target of rapamycin; PP2A, protein phosphatase 2A; PPARγ, peroxisome proliferator-activated receptor γ; SGLT2, sodium-dependent glucose transporter 2; TGFβ, tumor growth factor β; TNFα, tumor necrosis factor α; VGLUT, vesicular glutamate transporter.