Role of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) in diabetes mellitus

Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is a recently identified scavenger receptor expressed in endothelial cells and mediates the uptake of oxidized LDL (oxLDL). LOX-1 expression is increased in atherosclerotic lesions in animals and humans. Recent evidence has suggested that LOX-1 is involved in the development and progression of atherosclerosis. In addition to endothelial cells, it has also been reported that LOX-1 is also expressed by other cell types like macrophages. It is a multi-ligand class E scavenger receptor and cellular expression of LOX-1 can be induced by many of its ligands. The concentration of some of these ligands like oxLDL and advanced glycation end products (AGEs) are increased in the diabetic milieu. My hypothesis is that LOX-1 expression is increased in diabetes mellitus and LOX-1 activation may play a role in the development of micro- and/or macrovascular complications of diabetes. The objective of this thesis is to elucidate the role of LOX-1 in type 2 diabetes mellitus and its complications. The effect of modified LDL and AGEs on LOX-1 expression and the cellular response upon LOX-1 activation was investigated. In vitro studies have shown that both AGEs and oxLDL can activate and increase cellular expression of LOX-1 and the soluble form of LOX-1 (sLOX-1) in cultured endothelial cells. In addition, LDL modified by glycoxidation, is also a ligand of LOX-1 and glycoxidized LDL is even more potent than oxLDL in inducing LOX-1 expression. In patients with type 2 diabetes, serum level of sLOX-1 was significantly higher than non-diabetic normal control, indicating that LOX-1 expression was increased in diabetes. Serum levels of AGEs and glycoxidized LDL were important determinants of serum sLOX-1 level, and lowering serum AGEs led to a beneficial reduction in serum sLOX-1 concentration. Hence, AGEs was clearly an important ligand of LOX-1 in diabetes mellitus, and experiments were performed to further elucidate the underlying signaling pathway involved in the up-regulation of LOX-1 by AGEs. This was mediated by ligation of AGEs to the receptor for advanced glycation end products (RAGE) and activation of phosphoinositide 3-kinase. Mammalian target of rapamycin was a found to be a key downstream intermediary in AGEs-inducible LOX-1 expression in endothelial cells. I further demonstrated that LOX-1 was also expressed in human renal mesangial cells, and expression was at a low level at basal state but inducible by its ligands. Up-regulation of LOX-1 expression in activated mesangial cells resulted in increased oxidative stress, as well as increased production of proinflammatory cytokines, chemokines and growth factors. These experimental findings would suggest that LOX-1 might potentially be involved in renal inflammation and diabetic nephropathy. The above results collectively suggest that diabetes is associated with increased LOX-1 activation, and LOX-1 may play a role in the development of diabetic complications. Hence, LOX-1 might represent a suitable target for the future development of new strategies for treating and preventing diabetic vascular complications.published_or_final_versionMedicineDoctoralDoctor of Philosoph

Effect of type 2 diabetes on the inducible degrader of LDL receptor

The inducible degrader of LDL receptor (IDOL) acts as a post-transcriptional degrader of the LDL receptor (LDLR). IDOL is functionally active in the liver and in peripheral tissues. We have evaluated IDOL expression in circulating monocytes in subjects with and without type 2 diabetes and determined whether changes in IDOL expression could affect macrophage function like cytokine production in vitro. One hundred forty individuals with type 2 diabetes and 110 healthy control subjects were recruited. Cellular expression of IDOL and LDLR in peripheral blood CD14+ monocytes was measured by flow cytometry. The expression of intracellular IDOL was lower in individuals with diabetes than control (21.3 ± 4.6 mean fluorescence intensity × 1,000 vs. 23.8 ± 6.2, P < 0.01), and this was accompanied by an increase in cell surface LDLR (5.2 ± 3.0 mean fluorescence intensity × 1,000 vs. 4.3 ± 1.5, P < 0.01), LDL binding, and intracellular lipid (P < 0.01). IDOL expression correlated with HbA1c (r = −0.38, P < 0.01) and serum fibroblast growth factor-21 (FGF21) (r = −0.34, P < 0.01). Multivariable regression analysis, including age, sex, BMI, smoking, HbA1c, and log(FGF21), showed that HbA1c and FGF21 were significant independent determinants of IDOL expression. IDOL knockdown human monocyte-derived macrophages produced higher concentrations of interleukin 1 beta, interleukin 6, and TNFα than control macrophages upon stimulation with lipopolysaccharide (all P < 0.01). In conclusion, the expression of IDOL in CD14+ monocytes was decreased in type 2 diabetes and was associated with glycemia and serum FGF21 concentration