Lzp Ablation Ameliorates Dyslipidemia and Suppresses Atherosclerosis by Reducing Circulating Apolipoprotein B-Containing Lipoproteins

Abstract

As the principal regulator of systemic lipid homeostasis, the liver uniquely orchestrates dietary lipid assimilation, de novo lipogenesis, very-low-density lipoprotein (VLDL) assembly and secretion, and clearance of atherogenic lipoprotein remnants. This central role positions liver-specific molecular targets as critical therapeutic nodes for mitigating hyperlipidemia and halting atherosclerosis progression. The liver-specific protein Lzp (also named as OIT3), previously shown to stabilize apolipoprotein B (ApoB), the core structural component of triglyceride-rich lipoproteins, has an undefined role in vascular disease pathogenesis. Here, utilizing ApoE-/-mice, a well-established model that closely mimics human atherosclerosis, we demonstrate that Lzp deletion reduces plasma cholesterol, triglycerides, and ApoB levels under both chow and Western diets, concomitant with a marked attenuation of aortic plaque burden. Additionally, Lzp deficiency reduces hepatic and circulating ApoB levels in hyperlipidemic ApoE-/- mice, without exacerbating hepatic steatosis or injury. Mechanistically, Lzp ablation is anticipated to impair hepatic VLDL-ApoB secretion based on our previous findings, resulting in reduced circulating VLDL, intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL) particles, attenuated lipid deposition, and suppressed macrophage-driven plaque inflammation. These results underscore the role of Lzp as a key regulator of systemic lipid metabolism and identify it as a potential candidate for further investigation toward therapeutic intervention of atherosclerotic cardiovascular disease. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/678175v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@118ead8org.highwire.dtl.DTLVardef@e215baorg.highwire.dtl.DTLVardef@1007212org.highwire.dtl.DTLVardef@412757_HPS_FORMAT_FIGEXP M_FIG C_FIG HightlightsO_LILzp deficiency attenuates atherosclerosis and improves plasma lipid profiles in ApoE-/- mice fed chow or Western diets. C_LIO_LILzp deficiency reduces hepatic and circulating apolipoprotein B levels in hyperlipidemic ApoE-/- mice without exacerbating hepatic steatosis or injury. C_LIO_LILzp represents a candidate therapeutic target, warranting further mechanistic and translational studies for atherosclerosis. C_LI