ORMDL in Metabolic Health and Disease

Overview

Journal Pharmacol Ther

Specialty Pharmacology

Date 2023 Apr 1

PMID 37003301

Authors

Ryan D R Brown

Sarah Spiegel

Affiliations

Soon will be listed here.

Abstract

Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated fatty acids are substrates for serine palmitoyltransferase (SPT) the rate-limiting step in de novo sphingolipid biosynthesis. The mammalian orosomucoid-like protein isoforms ORMDL1-3 negatively regulate SPT activity. Here we summarize evidence that dysregulation of sphingolipid metabolism and SPT activity correlates with pathogenesis of obesity. This review also discusses the current understanding of the function of SPT and ORMDL in obesity and metabolic disease. Gaps and limitations in current knowledge are highlighted together with the need to further understand how ORMDL3, which has been identified as an obesity-related gene, contributes to the pathogenesis of obesity and development of metabolic disease related to its physiological functions. Finally, we point out the needs to move this young field of research forward.

Citing Articles

Sphingolipid metabolites involved in the pathogenesis of atherosclerosis: perspectives on sphingolipids in atherosclerosis.

Zhao F, Shao M, Li M, Li T, Zheng Y, Sun W Cell Mol Biol Lett. 2025; 30(1):18.

PMID: 39920588 PMC: 11804087. DOI: 10.1186/s11658-024-00679-2.

Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis.

Demkova L, Bugajev V, Adamcova M, Kuchar L, Grusanovic S, Alberich-Jorda M Front Immunol. 2024; 15:1376629.

PMID: 38715613 PMC: 11074395. DOI: 10.3389/fimmu.2024.1376629.

References

Blachnio-Zabielska A, Koutsari C, Tchkonia T, Jensen M . Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance. Obesity (Silver Spring). 2012; 20(12):2341-7. PMC: 3443533. DOI: 10.1038/oby.2012.126. View

Juchnicka I, Kuzmicki M, Szamatowicz J . Ceramides and Sphingosino-1-Phosphate in Obesity. Front Endocrinol (Lausanne). 2021; 12:635995. PMC: 8158155. DOI: 10.3389/fendo.2021.635995. View

Hajduch E, Lachkar F, Ferre P, Foufelle F . Roles of Ceramides in Non-Alcoholic Fatty Liver Disease. J Clin Med. 2021; 10(4). PMC: 7920467. DOI: 10.3390/jcm10040792. View

Hammerschmidt P, Bruning J . Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci. 2022; 79(8):395. PMC: 9252958. DOI: 10.1007/s00018-022-04401-3. View

Geng T, Sutter A, Harland M, Law B, Ross J, Lewin D . SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. J Lipid Res. 2015; 56(12):2359-71. PMC: 4655991. DOI: 10.1194/jlr.M063511. View

Kelpe C, Moore P, Parazzoli S, Wicksteed B, Rhodes C, Poitout V . Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem. 2003; 278(32):30015-21. DOI: 10.1074/jbc.M302548200. View

Xiong Y, Hla T . S1P control of endothelial integrity. Curr Top Microbiol Immunol. 2014; 378:85-105. PMC: 4240614. DOI: 10.1007/978-3-319-05879-5_4. View

Ma X, Qiu R, Dang J, Li J, Hu Q, Shan S . ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells. Sci Rep. 2015; 5:17194. PMC: 4658630. DOI: 10.1038/srep17194. View

Li Z, Kabir I, Tietelman G, Huan C, Fan J, Worgall T . Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function. Cell Death Dis. 2018; 9(2):173. PMC: 5833386. DOI: 10.1038/s41419-017-0214-1. View

10.

Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K . Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep. 2012; 2:799. PMC: 3495279. DOI: 10.1038/srep00799. View

11.

Lee S, Hong I, Kim B, Shim S, Lee J, Lee H . Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. Hepatology. 2015; 62(1):135-46. DOI: 10.1002/hep.27804. View

12.

Keppley L, Walker S, Gademsey A, Smith J, Keller S, Kester M . Nervonic acid limits weight gain in a mouse model of diet-induced obesity. FASEB J. 2020; 34(11):15314-15326. PMC: 8183615. DOI: 10.1096/fj.202000525R. View

13.

Green C, Maceyka M, Cowart L, Spiegel S . Sphingolipids in metabolic disease: The good, the bad, and the unknown. Cell Metab. 2021; 33(7):1293-1306. PMC: 8269961. DOI: 10.1016/j.cmet.2021.06.006. View

14.

Debeuf N, Zhakupova A, Steiner R, Van Gassen S, Deswarte K, Fayazpour F . The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice. J Allergy Clin Immunol. 2019; 144(6):1648-1659.e9. PMC: 7610749. DOI: 10.1016/j.jaci.2019.06.041. View

15.

Li J, Ullah M, Jin H, Liang Y, Lin L, Wang J . ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation an ATF6-UPR-Autophagy-Dependent Pathway. Front Immunol. 2021; 12:604974. PMC: 7933793. DOI: 10.3389/fimmu.2021.604974. View

16.

Spiegel S, Milstien S . The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011; 11(6):403-15. PMC: 3368251. DOI: 10.1038/nri2974. View

17.

Kuo A, Checa A, Niaudet C, Jung B, Fu Z, Wheelock C . Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis. Elife. 2022; 11. PMC: 9578713. DOI: 10.7554/eLife.78861. View

18.

Roelants F, Breslow D, Muir A, Weissman J, Thorner J . Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2011; 108(48):19222-7. PMC: 3228448. DOI: 10.1073/pnas.1116948108. View

19.

Lee S, Lee H, Song J, Kim G, Jeon S, Song Y . Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance. Diabetes. 2017; 66(10):2596-2609. PMC: 7970771. DOI: 10.2337/db16-1232. View

20.

Barbarroja N, Rodriguez-Cuenca S, Nygren H, Camargo A, Pirraco A, Relat J . Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function. Diabetes. 2014; 64(4):1180-92. PMC: 9757540. DOI: 10.2337/db14-0359. View