Recruiting a transcription factor in the liver to prevent atherosclerosis

Abstract

Hypertriglyceridemia is associated with obesity, diabetes, and atherosclerosis. While lipoprotein lipase (LPL) hydrolyzes triglyceride (TG) cargo into remnant lipoproteins with atherogenic properties, how remnant lipoprotein clearance relates to atherosclerosis in people with diabetes remains unclear. In this issue of the JCI, Shimizu-Albergine et al. examined the effects of the basic leucine zipper transcription factor CREBH, which induces genes that activate LPL in mouse models of type I diabetes. Overexpression of a CREBH fragment reduced apolipoprotein C3 (APOC3) levels, which reduced plasma TGs. Notably, the TGs were lowered by a mechanism that was independent of LPL, and atherosclerosis was alleviated by enhanced lipoprotein remnant clearance as opposed to increased lipolysis of TG-rich lipoprotein precursors. A proinflammatory mechanism likely underlies the atherogenicity of remnant lipoproteins. These findings suggest that modifying CREBH expression in the liver may ameliorate atherosclerosis and, perhaps, other diabetes complications.

Figure 1. Enhanced lipoprotein remnant clearance ameliorates atherosclerosis in mice ectopically expressing CREBH.

(A) In diabetes-related atherosclerosis, triglyceride-rich lipoproteins, VLDL, and chylomicrons (not shown) form remnant lipoproteins after lipoprotein lipase–mediated (LPL-mediated) triglyceride hydrolysis. Lipids associated with the lipoprotein particles are subject to oxidation. Oxidized lipids form complexes with proteins and bind to pattern recognition receptors on macrophages, inducing proinflammatory stimuli. Glucose can also form advanced glycosylation end products (AGEs), which bind to a distinct receptor for AGEs, termed RAGE. (B) Liver-specific expression of CREBH increases APOE, a ligand that mediates clearance of remnant particles and decreases APOC3, which can interfere with remnant clearance. CREBH also enhances the cell surface expression of the Lrp1 protein, one of several receptors that mediate remnant clearance. Clearance of remnant particles from the circulation reduces diabetes-related atherosclerosis. FFAs, free fatty acids.