Department of Cardiovascular Medicine, The Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, No.139 Middle Renmin Road, Changsha, 410011, Hunan, China.
Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
Cell Death Dis. 2024 Jun 3;15(6):389. doi: 10.1038/s41419-024-06778-4.
Apolipoprotein O (APOO) plays a critical intracellular role in regulating lipid metabolism. Here, we investigated the roles of APOO in metabolism and atherogenesis in mice. Hepatic APOO expression was increased in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout (Apoo) model, it was found that APOO depletion aggravated diet-induced obesity and elevated plasma cholesterol levels. Upon crossing with low-density lipoprotein receptor (LDLR) and apolipoprotein E (APOE) knockout hyperlipidemic mouse models, Apoo Apoe and Apoo Ldlr mice exhibited elevated plasma cholesterol levels, with more severe atherosclerotic lesions than littermate controls. This indicated the effects of APOO on cholesterol metabolism independent of LDLR and APOE. Moreover, APOO deficiency reduced cholesterol excretion through bile and feces while decreasing phospholipid unsaturation by inhibiting NRF2 and CYB5R3. Restoration of CYB5R3 expression in vivo by adeno-associated virus (AAV) injection reversed the reduced degree of phospholipid unsaturation while decreasing blood cholesterol levels. This represents the first in vivo experimental validation of the role of APOO in plasma cholesterol metabolism independent of LDLR and elucidates a previously unrecognized cholesterol metabolism pathway involving NRF2/CYB5R3. APOO may be a metabolic regulator of total-body cholesterol homeostasis and a target for atherosclerosis management. Apolipoprotein O (APOO) regulates plasma cholesterol levels and atherosclerosis through a pathway involving CYB5R3 that regulates biliary and fecal cholesterol excretion, independently of the LDL receptor. In addition, down-regulation of APOO may lead to impaired mitochondrial function, which in turn aggravates diet-induced obesity and fat accumulation.
载脂蛋白 O (APOO) 在调节脂质代谢中发挥着重要的细胞内作用。在这里，我们研究了 APOO 在小鼠代谢和动脉粥样硬化形成中的作用。高脂血症时肝 APOO 表达增加，但辛伐他汀治疗后则受到抑制。利用新型 APOO 基因敲除（Apoo）模型，发现 APOO 缺失加剧了饮食诱导的肥胖和血浆胆固醇水平升高。与低密度脂蛋白受体（LDLR）和载脂蛋白 E（APOE）敲除高脂血症小鼠模型杂交后，Apoo Apoe 和 Apoo Ldlr 小鼠的血浆胆固醇水平升高，动脉粥样硬化病变比同窝对照更严重。这表明 APOO 对胆固醇代谢的影响独立于 LDLR 和 APOE。此外，APOO 缺乏通过抑制 NRF2 和 CYB5R3 减少胆固醇通过胆汁和粪便排泄，并降低磷脂不饱和程度。腺相关病毒（AAV）注射体内恢复 CYB5R3 表达，逆转了磷脂不饱和程度的降低，同时降低了血液胆固醇水平。这是 APOO 独立于 LDLR 参与血浆胆固醇代谢的体内实验的首次验证，并阐明了一条以前未被认识到的涉及 NRF2/CYB5R3 的胆固醇代谢途径。APOO 可能是全身胆固醇稳态的代谢调节剂，也是动脉粥样硬化管理的靶点。
