Chen Fengwu, Yang Aizhen, Lu Yue, Zhang Yuxin, Zhang Jingyu, Bu Jianan, Guo Runlin, Han Yue, Wu Depei, Wu Yi
National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, 215123, China.
The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
Nat Commun. 2025 Feb 4;16(1):1344. doi: 10.1038/s41467-025-56620-4.
Saturated fatty acid (SFA) and unsaturated fatty acid (UFA) have distinct impacts on health. Whether SFA and UFA are differentially transported in liver remains elusive. Here, we find the secretion of UFA but not SFA esters is retarded in a male mouse hepatic endoplasmic reticulum (ER) stress model. Among 13 members of protein disulfide isomerase (PDI) family, only PDIA1 (PDI) deficiency leads to hepatosteatosis and hypolipidemia. In PDI-deficient male mouse liver, there is a severe accumulation but secretory blockade of UFA esters, whereas the accumulation and secretion of SFA esters remain normal. PDI catalyzes the oxidative folding of microsomal triglyceride transfer protein (MTP). In addition, PDI deficiency in hepatocytes abolishes Apolipoprotein B-100 (ApoB-100) very low-density lipoprotein (VLDL) secretion while maintaining partial ApoB-48 VLDL secretion. In summary, we find that the secretion of UFA esters is PDI-MTP indispensable, while SFA esters could be transferred out of liver via ApoB-48 VLDL through a PDI-MTP-independent pathway.
饱和脂肪酸（SFA）和不饱和脂肪酸（UFA）对健康有不同影响。SFA和UFA在肝脏中是否存在差异转运仍不清楚。在此，我们发现在雄性小鼠肝脏内质网（ER）应激模型中，UFA酯而非SFA酯的分泌受到阻碍。在蛋白质二硫键异构酶（PDI）家族的13个成员中，只有PDIA1（PDI）缺乏会导致肝脂肪变性和低脂血症。在PDI缺乏的雄性小鼠肝脏中，UFA酯存在严重蓄积但分泌受阻，而SFA酯的蓄积和分泌仍正常。PDI催化微粒体甘油三酯转移蛋白（MTP）的氧化折叠。此外，肝细胞中PDI缺乏会消除载脂蛋白B-100（ApoB-100）极低密度脂蛋白（VLDL）的分泌，同时维持部分ApoB-48 VLDL的分泌。总之，我们发现UFA酯的分泌离不开PDI-MTP，而SFA酯可通过独立于PDI-MTP的途径经ApoB-48 VLDL转运出肝脏。
