Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism 2019; 92: 82–97

    Article  CAS  PubMed  Google Scholar 

  2. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 2019; 15(5): 288–298

    Article  PubMed  Google Scholar 

  3. Piché ME, Tchernof A, Després JP. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ Res 2020; 126(11): 1477–1500

    Article  PubMed  Google Scholar 

  4. Tsai AG, Bessesen DH. Obesity. Ann Intern Med 2019; 170(5): ITC33–ITC48

    Article  PubMed  Google Scholar 

  5. Goodarzi MO. Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. Lancet Diabetes Endocrinol 2018; 6(3): 223–236

    Article  CAS  PubMed  Google Scholar 

  6. Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med 2015; 373(10): 895–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xiang R, Fan LL, Huang H, Chen YQ, He W, Guo S, Li JJ, Jin JY, Du R, Yan R, Xia K. Increased reticulon 3 (RTN3) leads to obesity and hypertriglyceridemia by interacting with heat shock protein family A (Hsp70) member 5 (HSPA5). Circulation 2018; 138(17): 1828–1838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen C, Wang H, Chen B, Chen D, Lu C, Li H, Qian Y, Tan Y, Weng H, Cai L. Pex11a deficiency causes dyslipidaemia and obesity in mice. J Cell Mol Med 2019; 23(3): 2020–2031

    Article  CAS  PubMed  Google Scholar 

  9. Lei X, Wong GW. C1q/TNF-related protein 2 (CTRP2) deletion promotes adipose tissue lipolysis and hepatic triglyceride secretion. J Biol Chem 2019; 294(43): 15638–15649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Moslehi A, Hamidi-Zad Z. Role of SREBPs in liver diseases: a mini-review. J Clin Transl Hepatol 2018; 6(3): 332–338

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hauck AK, Huang Y, Hertzel AV, Bernlohr DA. Adipose oxidative stress and protein carbonylation. J Biol Chem 2019; 294(4): 1083–1088

    Article  CAS  PubMed  Google Scholar 

  12. de Mello AH, Costa AB, Engel JDG, Rezin GT. Mitochondrial dysfunction in obesity. Life Sci 2018; 192: 26–32

    Article  CAS  PubMed  Google Scholar 

  13. Han L, Shen WJ, Bittner S, Kraemer FB, Azhar S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-a. Future Cardiol 2017; 13(3): 259–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Reue K. The lipin family: mutations and metabolism. Curr Opin Lipidol 2009; 20(3): 165–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JCJr, Kelly DP. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006; 4(3): 199–210

    Article  CAS  PubMed  Google Scholar 

  16. Chen Y, Rui BB, Tang LY, Hu CM. Lipin family proteins-key regulators in lipid metabolism. Ann Nutr Metab 2015; 66(1): 10–18

    Article  CAS  PubMed  Google Scholar 

  17. Romani P, Brian I, Santinon G, Pocaterra A, Audano M, Pedretti S, Mathieu S, Forcato M, Bicciato S, Manneville JB, Mitro N, Dupont S. Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP. Nat Cell Biol 2019; 21(3): 338–347

    Article  CAS  PubMed  Google Scholar 

  18. Casas J, Meana C, López-López JR, Balsinde J, Balboa MA. Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling. Cell Mol Life Sci 2021; 78(24): 8243–8260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chae M, Jung JY, Bae IH, Kim HJ, Lee TR, Shin DW. Lipin-1 expression is critical for keratinocyte differentiation. J Lipid Res 2016; 57(4): 563–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reue K, Zhang P. The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett 2008; 582(1): 90–96

    Article  CAS  PubMed  Google Scholar 

  21. Fan LL, Ding DB, Huang H, Chen YQ, Jin JY, Xia K, Xiang R. A de novo mutation of SMYD1 (p. F272L) is responsible for hypertrophic cardiomyopathy in a Chinese patient. Clin Chem Lab Med 2019; 57(4): 532–539

    Article  CAS  PubMed  Google Scholar 

  22. Huang H, Guo S, Chen YQ, Liu YX, Jin JY, Liang Y, Fan LL, Xiang R. Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK-IDH2 pathway. MedComm (2020) 2023; 4(2): e226

    CAS  PubMed  Google Scholar 

  23. Shi Q, Ge Y, Sharoar MG, He W, Xiang R, Zhang Z, Hu X, Yan R. Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci 2014; 34(42): 13954–13962

    Article  PubMed  PubMed Central  Google Scholar 

  24. Csaki LS, Dwyer JR, Li X, Nguyen MH, Dewald J, Brindley DN, Lusis AJ, Yoshinaga Y, de Jong P, Fong L, Young SG, Reue K. Lipin-1 and lipin-3 together determine adiposity in vivo. Mol Metab 2014; 3(2): 145–154

    Article  CAS  PubMed  Google Scholar 

  25. Péterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 2001; 27(1): 121–124

    Article  PubMed  Google Scholar 

  26. Bi L, Jiang Z, Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver. Alcohol Alcohol 2015; 50(2): 146–151

    Article  CAS  PubMed  Google Scholar 

  27. Barroso E, Astudillo AM, Balsinde J, Vázquez-Carrera M. PPARβ/δ Activation prevents hypertriglyceridemia caused by a high fat diet. Involvement of AMPK and PGC-1α-Lipin1-PPARα pathway. Clin Investig Arterioscler 2013; 25(2): 63–73 (in Spanish)

    PubMed  Google Scholar 

  28. Kim HL, Park J, Park H, Jung Y, Youn DH, Kang J, Jeong MY, Um JY. Platycodon grandiflorum A. De Candolle ethanolic extract inhibits adipogenic regulators in 3T3-L1 cells and induces mitochondrial biogenesis in primary brown preadipocytes. J Agric Food Chem 2015; 63(35): 7721–7730

    Article  CAS  PubMed  Google Scholar 

  29. Bi L, Jiang Z, Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver. Alcohol Alcohol 2015; 50(2): 146–151

    Article  CAS  PubMed  Google Scholar 

  30. De Rasmo D, Signorile A, De Leo E, Polishchuk EV, Ferretta A, Raso R, Russo S, Polishchuk R, Emma F, Bellomo F. Mitochondrial dynamics of proximal tubular epithelial cells in nephropathic cystinosis. Int J Mol Sci 2019; 21(1): 192

    Article  PubMed  PubMed Central  Google Scholar 

  31. Serasinghe MN, Chipuk JE. Mitochondrial fission in human diseases. Handb Exp Pharmacol 2017; 240: 159–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Michot C, Hubert L, Romero NB, Gouda A, Mamoune A, Mathew S, Kirk E, Viollet L, Rahman S, Bekri S, Peters H, McGill J, Glamuzina E, Farrar M, von der Hagen M, Alexander IE, Kirmse B, Barth M, Laforet P, Benlian P, Munnich A, JeanPierre M, Elpeleg O, Pines O, Delahodde A, de Keyzer Y, de Lonlay P. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis 2012; 35(6): 1119–1128

    Article  CAS  PubMed  Google Scholar 

  33. Pennisi EM, Garibaldi M, Antonini G. Lipid myopathies. J Clin Med 2018; 7(12): 472

    Article  PubMed  PubMed Central  Google Scholar 

  34. Reue K, Brindley DN. Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J Lipid Res 2008; 49(12): 2493–2503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rashid T, Nemazanyy I, Paolini C, Tatsuta T, Crespin P, de Villeneuve D, Brodesser S, Benit P, Rustin P, Baraibar MA, Agbulut O, Olivier A, Protasi F, Langer T, Chrast R, de Lonlay P, de Foucauld H, Blaauw B, Pende M. Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. EMBO J 2019; 38(1): e99576

    Article  PubMed  Google Scholar 

  36. Watahiki A, Hoshikawa S, Chiba M, Egusa H, Fukumoto S, Inuzuka H. Deficiency of Lipin2 results in enhanced NF-κB signaling and osteoclast formation in RAW-D murine macrophages. Int J Mol Sci 2021; 22(6): 2893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bou Khalil M, Blais A, Figeys D, Yao Z. Lipin — the bridge between hepatic glycerolipid biosynthesis and lipoprotein metabolism. Biochim Biophys Acta 2010; 1801(12): 1249–1259

    Article  PubMed  Google Scholar 

  38. Zhang P, Csaki LS, Ronquillo E, Baufeld LJ, Lin JY, Gutierrez A, Dwyer JR, Brindley DN, Fong LG, Tontonoz P, Young SG, Reue K. Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis. J Clin Invest 2019; 129(1): 281–295

    Article  PubMed  Google Scholar 

  39. Simóes ICM, Fontes A, Pinton P, Zischka H, Wieckowski MR. Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol 2018; 95: 93–99

    Article  PubMed  Google Scholar 

  40. Mazat JP, Devin A, Ransac S. Modelling mitochondrial ROS production by the respiratory chain. Cell Mol Life Sci 2020; 77(3): 455–465

    Article  CAS  PubMed  Google Scholar 

  41. Rives C, Fougerat A, Ellero-Simatos S, Loiseau N, Guillou H, Gamet-Payrastre L, Wahli W. Oxidative stress in NAFLD: role of nutrients and food contaminants. Biomolecules 2020; 10(12): 1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kakehi S, Tamura Y, Ikeda SI, Kaga N, Taka H, Ueno N, Shiuchi T, Kubota A, Sakuraba K, Kawamori R, Watada H. Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation. Am J Physiol Endocrinol Metab 2021; 321(6): E766–E781

    Article  CAS  PubMed  Google Scholar 

  43. Zhang P, Takeuchi K, Csaki LS, Reue K. Lipin-1 phosphatidic phosphatase activity modulates phosphatidate levels to promote peroxisome proliferator-activated receptor γ (PPARγ) gene expression during adipogenesis. J Biol Chem 2012; 287(5): 3485–3494

    Article  CAS  PubMed  Google Scholar 

  44. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013; 25(10): 1939–1948

    Article  CAS  PubMed  Google Scholar 

  45. Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, De Bosscher K. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr Rev 2018; 39(5): 760–802

    Article  PubMed  Google Scholar 

Download references

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).

Author information

Author notes

  1. Contributed equally.

Authors and Affiliations

  1. Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China

    Fang Wang, Yuxing Liu, Liangliang Fan & Rong Xiang

  2. Department of Cellular Biology, School of Life Sciences, Key Laboratory of Pediatric Rare Diseases, Ministry of Education, Central South University, Changsha, 410013, China

    Yuxing Liu, Yi Dong, Meifang Zhao, Hao Huang, Jieyuan Jin, Liangliang Fan & Rong Xiang

Authors
  1. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meifang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jieyuan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liangliang Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Liangliang Fan or Rong Xiang.

Ethics declarations

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.

Electronic supplementary material

11684_2023_1003_MOESM1_ESM.pdf

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, F., Liu, Y., Dong, Y. et al. Haploinsufficiency of Lipin3 leads to hypertriglyceridemia and obesity by disrupting the expression and nucleocytoplasmic localization of Lipin1. Front. Med. 18, 180–191 (2024). https://doi.org/10.1007/s11684-023-1003-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-023-1003-0

Keywords

Search

Navigation