Editorial

Sonic Hedgehog Signaling, Lipids, and Metabolic Disorders

Please cite this article as follows: Tayebinia H. Sonic hedgehog signaling, lipids, and metabolic disorders. Avicenna J Med Biochem. 2023; 11(2):100-101. doi:10.34172/ajmb.2488

The hedgehog (HH) gene was first discovered in Drosophila for its role in embryonic development; however, it plays a crucial and conserved role in numerous processes of vertebrates, such as embryogenesis, epithelial-mesenchymal transition, and cellular development (1-3). Secreted HH ligands can diffuse through the extracellular matrix to act on distant cells (4). In this regard, three homologous ligands for HH have been identified in mammals, including desert (DHH), sonic (SHH), and Indian (IHH) HH ligands (5,6). The interaction of the SHH ligand with the Patched receptor (PTCH1) on recipient cells activates the smoothen (SMO) by relieving its suppression and subsequently activates transcription factors in the glioma-associated oncogene family (7). Recent findings have suggested that there is an interaction between the SHH pathway and other signaling pathways, including Wnt/β-catenin, transforming growth factor β, mammalian target of rapamycin, and notch (8).

Evidence implies that the disruption of HH signaling is effectively involved in developing cancers in various organs (9). In this regard, recent studies have revealed that patients with mutations resulting in the impaired activity of SHH signaling effectors Patched and SMO may develop basal-cell carcinomas (10). On the other hand, an impairment in the pathway has been found to cause various metabolic disorders. It has been suggested that impairments in the HH signaling pathways may contribute to several lipid/lysosomal storage disorder diseases, such as Niemann-Pick C 1 and 2 (NPC1, 2) and mucopolysaccharidosis type II (Hunter disease) (10,11).

HH signaling as a morphogen signaling is tightly regulated with unique modifications. The modification of SHH with cholesterol, at the C terminus and palmitate at the N terminus, ensures the SHH trafficking to plasma membranes (12). Lipid modifications also enhance the SHH transporting across the plasma membrane for release extracellularly (13,14). Recent evidence suggests that the lipid moieties attached to SHH play an important role in the interaction between this ligand and the PTCH1 receptor (15). Interactions of the palmitoylated N-terminal of the SHH ligand with PTCH1 are crucial for the inhibition of PTCH1, thus triggering HH signaling via SMO (16). Therefore, inhibiting the PTCH1 receptor on SMO is lost in the presence of cholesterol and 7 -dehydrocholesterol-derived oxysterols (17). However, the biding of synthetic and endogenous oxysterols with the extracellular cysteine-rich domain can allosterically activate SMO (18), and cholesterol as an endogenous activator of SMO can stimulate SHH signaling independently (13). During the SHH signaling, SMO trafficking to the primary cilium is shown to be aided by cholesterol derivatives and oxysterols. This implies the crucial role of cholesterol and other lipids in the activation of the SHH signaling pathway in various organs. Owing to the importance of SHH signaling in metabolic disorders, it seems that cholesterol metabolism might play a critical role in the development of metabolic disorders by the interaction of SHH signaling.

Experimental studies demonstrated that the HH pathway ligand is overexpressed in non-alcoholic steatohepatitis (NASH) specimens. Additionally, it has been reported that the severity of liver disease is directly related to the activity of the SHH pathway in non-alcoholic fatty liver disease (19). However, studies on the liver tissue of patients with simple steatosis revealed that the SHH signaling pathway was downregulated in simple steatosis as compared to NASH-related cirrhosis (20).

Taken together, the possibility of the lipid modification of SHH, PTCH, and SMO, the key signal transducers in the SHH signaling pathway, through different lipid species and cholesterol, might explain why lipid metabolism is associated with an impaired SHH signaling pathway and subsequently their roles in metabolic disorders.

Competing Interests

None.

Ethical Approval

Not applicable.

References

1. Ingham PW. Hedgehog signaling. Curr Top Dev Biol 2022; 149:1-58. doi: 10.1016/bs.ctdb.2022.04.003 [Crossref] [ Google Scholar]
2. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 2014; 7(344):re8. doi: 10.1126/scisignal.2005189 [Crossref] [ Google Scholar]
3. Jing J, Wu Z, Wang J, Luo G, Lin H, Fan Y. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduct Target Ther 2023; 8(1):315. doi: 10.1038/s41392-023-01559-5 [Crossref] [ Google Scholar]
4. Qi X, Li X. Mechanistic insights into the generation and transduction of hedgehog signaling. Trends Biochem Sci 2020; 45(5):397-410. doi: 10.1016/j.tibs.2020.01.006 [Crossref] [ Google Scholar]
5. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15(23):3059-87. doi: 10.1101/gad.938601 [Crossref] [ Google Scholar]
6. Qi C, Di Minin G, Vercellino I, Wutz A, Korkhov VM. Structural basis of sterol recognition by human hedgehog receptor PTCH1. Sci Adv 2019; 5(9):eaaw6490. doi: 10.1126/sciadv.aaw6490 [Crossref] [ Google Scholar]
7. Pietrobono S, Gagliardi S, Stecca B. Non-canonical hedgehog signaling pathway in cancer: activation of GLI transcription factors beyond smoothened. Front Genet 2019; 10:556. doi: 10.3389/fgene.2019.00556 [Crossref] [ Google Scholar]
8. Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-β pathways impinge on hedgehog signaling complexity: an open window on cancer. Front Genet 2019; 10:711. doi: 10.3389/fgene.2019.00711 [Crossref] [ Google Scholar]
9. Machado MV, Diehl AM. Hedgehog signaling in liver pathophysiology. J Hepatol 2018; 68(3):550-62. doi: 10.1016/j.jhep.2017.10.017 [Crossref] [ Google Scholar]
10. Garg C, Khan H, Kaur A, Singh TG, Sharma VK, Singh SK. Therapeutic implications of sonic hedgehog pathway in metabolic disorders: novel target for effective treatment. Pharmacol Res 2022; 179:106194. doi: 10.1016/j.phrs.2022.106194 [Crossref] [ Google Scholar]
11. Fiorenza MT, Moro E, Erickson RP. The pathogenesis of lysosomal storage disorders: beyond the engorgement of lysosomes to abnormal development and neuroinflammation. Hum Mol Genet 2018; 27(R2):R119-29. doi: 10.1093/hmg/ddy155 [Crossref] [ Google Scholar]
12. Peters C, Wolf A, Wagner M, Kuhlmann J, Waldmann H. The cholesterol membrane anchor of the hedgehog protein confers stable membrane association to lipid-modified proteins. Proc Natl Acad Sci U S A 2004; 101(23):8531-6. doi: 10.1073/pnas.0308449101 [Crossref] [ Google Scholar]
13. Blassberg R, Jacob J. Lipid metabolism fattens up hedgehog signaling. BMC Biol 2017; 15(1):95. doi: 10.1186/s12915-017-0442-y [Crossref] [ Google Scholar]
14. Daggubati V, Raleigh DR, Sever N. Sterol regulation of developmental and oncogenic hedgehog signaling. Biochem Pharmacol 2022; 196:114647. doi: 10.1016/j.bcp.2021.114647 [Crossref] [ Google Scholar]
15. Wierbowski BM, Petrov K, Aravena L, Gu G, Xu Y, Salic A. Hedgehog pathway activation requires coreceptor-catalyzed, lipid-dependent relay of the sonic hedgehog ligand. Dev Cell 2020;55(4):450-67.e8. 10.1016/j.devcel.2020.09.017.
16. Tukachinsky H, Petrov K, Watanabe M, Salic A. Mechanism of inhibition of the tumor suppressor patched by sonic hedgehog. Proc Natl Acad Sci U S A 2016; 113(40):E5866-75. doi: 10.1073/pnas.1606719113 [Crossref] [ Google Scholar]
17. Myers BR, Sever N, Chong YC, Kim J, Belani JD, Rychnovsky S. Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev Cell 2013; 26(4):346-57. doi: 10.1016/j.devcel.2013.07.015 [Crossref] [ Google Scholar]
18. Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K. Structure and function of the Smoothened extracellular domain in vertebrate hedgehog signaling. Elife 2013; 2:e01340. doi: 10.7554/eLife.01340 [Crossref] [ Google Scholar]
19. Mohagheghi S, Khajehahmadi Z, Tavilani H. Signaling in simple steatosis and non-alcoholic steatohepatitis cirrhosis: TGF-β1, YAP/TAZ, and hedgehog pathway activity. Avicenna J Med Biochem 2018; 6(2):26-30. doi: 10.15171/ajmb.2018.07 [Crossref] [ Google Scholar]
20. Khajehahmadi Z, Mohagheghi S, Nikeghbalian S, Geramizadeh B, Khodadadi I, Karimi J. Downregulation of hedgehog ligands in human simple steatosis may protect against nonalcoholic steatohepatitis: is TAZ a crucial regulator?. IUBMB Life 2019; 71(9):1382-90. doi: 10.1002/iub.2068 [Crossref] [ Google Scholar]