LDL and apoB
CETP expression abolishes the atheroprotective effect of large HDL particles in mouse models of type 1 diabetes (Circ Res 2024)
Original title: Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis
Since people with type 1 diabetes have normal or higher HDL cholesterol yet face increased atherosclerotic cardiovascular risk, researchers created LDL-receptor-deficient mice expressing human apolipoprotein A1 to model human-like HDL subspecies in diabetes, with or without CETP expression. Diabetic mice without CETP had markedly elevated plasma apoB but were protected from the proatherogenic effects of diabetes; adding CETP expression, which lowered concentrations of large HDL subspecies, abolished this protection, increasing lesion necrotic core area and apoB accumulation despite lower plasma apoB levels. This detrimental effect of CETP was not explained by reduced cholesterol efflux but by large HDL's superior ability to block scavenger-receptor-B1-mediated endothelial transcytosis of LDL, and in humans with type 1 diabetes, higher concentrations of larger HDL particles relative to apoB100 independently predicted lower incident cardiovascular disease, indicating that the balance between apoB lipoproteins and large HDL, rather than HDL cholesterol level alone, drives atherosclerosis in type 1 diabetes.
Original abstract
Background: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D.
Methods: We generated LDL receptor-deficient (Ldlr-/-) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr-/-APOA1Tg mice exhibited the main human HDL subspecies. We also generated Ldlr-/-APOA1Tg T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy.
Results: Diabetic Ldlr-/-APOA1Tg mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic Ldlr-/-APOA1Tg mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDL particles relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels.
Conclusions: Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.
diabetesHDL biologyLDL and apoBmechanisms
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.