Haploinsufficiency of Lipin3 leads to hypertriglyceridemia and obesity by disrupting the expression and nucleocytoplasmic localization of Lipin1
Fang Wang1, Yuxing Liu1,2, Yi Dong2, Meifang Zhao2, Hao Huang2, Jieyuan Jin2, Liangliang Fan1,2(), Rong Xiang1,2()
1. Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha 410013, China 2. Department of Cellular Biology, School of Life Sciences, Key Laboratory of Pediatric Rare Diseases, Ministry of Education, Central South University, Changsha 410013, China
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.
. [J]. Frontiers of Medicine, 2024, 18(1): 180-191.
Fang Wang, Yuxing Liu, Yi Dong, Meifang Zhao, Hao Huang, Jieyuan Jin, Liangliang Fan, Rong Xiang. Haploinsufficiency of Lipin3 leads to hypertriglyceridemia and obesity by disrupting the expression and nucleocytoplasmic localization of Lipin1. Front. Med., 2024, 18(1): 180-191.
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