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

作者：Kunyan He, Xin Ku, Ziyao Chen, Chenyue Wu, C. Liao, Lin Li, Hongjin Qu, Peicheng Hong, Shihao Bai, Xiaofang Cui, Xianbin Su, Ze-Guang Han · 发表于：bioRxiv · 年份：2025 · DOI：10.1101/2025.09.24.678175 · 研究领域：Biology

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 ide...