Haploinsufficiency of Lipin3 leads to hypertriglyceridemia and obesity by disrupting the expression and nucleocytoplasmic localization of Lipin1

Abstract

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.

Keywords

Lipin3 / Lipin1 / hypertriglyceridemia / obesity / mitochondrial dysfunction

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Acknowledgements

The authors thank the patients and their families for participating in this study. They also gratefully acknowledge Prof. Riqiang Yan of Uconn Health for antibody and technical assistance. This study was supported by the National Natural Science Foundation of China (Nos. 82170598, 82000427, and 81970403), the Key Research and Development Program of Hunan Province (No. 2022sk2034), and the Natural Science Foundation of Hunan Province (Nos. 2022JJ30058 and 2023JJ20078).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1003-0 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Fang Wang, Yuxing Liu, Yi Dong, Meifang Zhao, Hao Huang, Jieyuan Jin, Liangliang Fan, and Rong Xiang declare no conflicts of interest pertaining to this work.

The study was approved by the authors’ Institutional Review Board (the Third Xiangya Hospital of Central South University, approval no. 2020-S533, date 2020.9.15) and the study was performed in accordance with the ethical standards as laid down in the 1964 and its later amendments or comparable ethical standards. Informed consent was obtained from all individuals included in this study.

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