Figure 1: A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intraretinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.