Wang Fang, Liu Yuxing, Dong Yi, Zhao Meifang, Huang Hao, Jin Jieyuan, Fan Liangliang, Xiang Rong
Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
Department of Cellular Biology, School of Life Sciences, Key Laboratory of Pediatric Rare Diseases, Ministry of Education, Central South University, Changsha, 410013, China.
Front Med. 2024 Feb;18(1):180-191. doi: 10.1007/s11684-023-1003-0. Epub 2023 Sep 30.
Lipin proteins including Lipin 1-3 act as transcriptional co-activators and phosphatidic acid phosphohydrolase enzymes, which play crucial roles in lipid metabolism. However, little is known about the function of Lipin3 in triglyceride (TG) metabolism. Here, we identified a novel mutation (NM_001301860: p.1835A>T/p.D612V) of Lipin3 in a large family with hypertriglyceridemia (HTG) and obesity through whole-exome sequencing and Sanger sequencing. Functional studies revealed that the novel variant altered the half-life and stability of the Lipin3 protein. Hence, we generated Lipin3 heterozygous knockout (Lipin3-heKO) mice and cultured primary hepatocytes to explore the pathophysiological roles of Lipin3 in TG metabolism. We found that Lipin3-heKO mice exhibited obvious obesity, HTG, and non-alcoholic fatty liver disorder. Mechanistic study demonstrated that the haploinsufficiency of Lipin3 in primary hepatocytes may induce the overexpression and abnormal distribution of Lipin1 in cytosol and nucleoplasm. The increased expression of Lipin1 in cytosol may contribute to TG anabolism, and the decreased Lipin1 in nucleoplasm can reduce PGC1α, further leading to mitochondrial dysfunction and reduced TG catabolism. Our study suggested that Lipin3 was a novel disease-causing gene inducing obesity and HTG. We also established a relationship between Lipin3 and mitochondrial dysfunction.
包括脂联蛋白1-3在内的脂联蛋白发挥转录共激活因子和磷脂酸磷酸水解酶的作用，在脂质代谢中起关键作用。然而，关于脂联蛋白3在甘油三酯（TG）代谢中的功能知之甚少。在此，我们通过全外显子测序和桑格测序，在一个患有高甘油三酯血症（HTG）和肥胖症的大家族中鉴定出脂联蛋白3的一个新突变（NM_001301860: p.1835A>T/p.D612V）。功能研究表明，该新变体改变了脂联蛋白3蛋白的半衰期和稳定性。因此，我们构建了脂联蛋白3杂合敲除（Lipin3-heKO）小鼠并培养原代肝细胞，以探索脂联蛋白3在TG代谢中的病理生理作用。我们发现Lipin3-heKO小鼠表现出明显的肥胖、HTG和非酒精性脂肪性肝病。机制研究表明，原代肝细胞中脂联蛋白3的单倍体不足可能诱导脂联蛋白1在细胞质和核质中的过表达和异常分布。细胞质中脂联蛋白1表达的增加可能有助于TG的合成代谢，核质中脂联蛋白1的减少会降低PGC1α，进而导致线粒体功能障碍和TG分解代谢减少。我们的研究表明，脂联蛋白3是一种导致肥胖和HTG的新致病基因。我们还建立了脂联蛋白3与线粒体功能障碍之间的关系。
