Palmitoylation of PKCδ by ZDHHC5 in Hypothalamic Microglia Presents As a Therapeutic Target for Fatty Liver Disease

Overview

Journal Theranostics

Date 2024 Jan 22

PMID 38250049

Authors

Yan-Hang Wang

Xin Chen

Yi-Zhen Bai

Peng Gao

Zhuo Yang

Qiang Guo

Ying-Yuan Lu

Jiao Zheng

Dan Liu

Jun Yang

Peng-Fei Tu

Ke-Wu Zeng

Affiliations

Soon will be listed here.

Abstract

The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.

References

Varga A, Gyulavari P, Greff Z, Futosi K, Nemeth T, Simon-Szabo L . Targeting vascular endothelial growth factor receptor 2 and protein kinase D1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro. PLoS One. 2015; 10(4):e0124234. PMC: 4396990. DOI: 10.1371/journal.pone.0124234. View

Perrin J, Werner T, Kurzawa N, Rutkowska A, Childs D, Kalxdorf M . Identifying drug targets in tissues and whole blood with thermal-shift profiling. Nat Biotechnol. 2020; 38(3):303-308. DOI: 10.1038/s41587-019-0388-4. View

Zhang L, Qian Y, Li J, Zhou X, Xu H, Yan J . BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology. iScience. 2021; 24(9):102942. PMC: 8369003. DOI: 10.1016/j.isci.2021.102942. View

Martinez-Sanchez N, Seoane-Collazo P, Contreras C, Varela L, Villarroya J, Rial-Pensado E . Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. Cell Metab. 2017; 26(1):212-229.e12. PMC: 5501726. DOI: 10.1016/j.cmet.2017.06.014. View

Zheng T, Yang X, Li W, Wang Q, Chen L, Wu D . Salidroside Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease via AMPK-Dependent TXNIP/NLRP3 Pathway. Oxid Med Cell Longev. 2018; 2018:8597897. PMC: 6081551. DOI: 10.1155/2018/8597897. View

Harrison S, Bashir M, Guy C, Zhou R, Moylan C, Frias J . Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019; 394(10213):2012-2024. DOI: 10.1016/S0140-6736(19)32517-6. View

Seo M, Choi H, Jeon H, Woo M, Lee B . Baicalein inhibits lipid accumulation by regulating early adipogenesis and m-TOR signaling. Food Chem Toxicol. 2014; 67:57-64. DOI: 10.1016/j.fct.2014.02.009. View

Hameed S, Patterson M, Dhillo W, Rahman S, Ma Y, Holton C . Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight. Cell Rep. 2017; 19(11):2202-2209. PMC: 5478879. DOI: 10.1016/j.celrep.2017.05.066. View

Ndoja A, Reja R, Lee S, Webster J, Ngu H, Rose C . Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia. Cell. 2020; 182(5):1156-1169.e12. DOI: 10.1016/j.cell.2020.07.011. View

10.

Abramson E, Hardman C, Shimizu A, Hwang S, Hester L, Snyder S . Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation. Cell Chem Biol. 2021; 28(4):537-545.e4. PMC: 8052272. DOI: 10.1016/j.chembiol.2020.12.015. View

11.

Pappa H, Dekker L, Parker P, McDonald N . Crystal structure of the C2 domain from protein kinase C-delta. Structure. 1998; 6(7):885-94. DOI: 10.1016/s0969-2126(98)00090-2. View

12.

Coll R, Hill J, Day C, Zamoshnikova A, Boucher D, Massey N . MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 2019; 15(6):556-559. DOI: 10.1038/s41589-019-0277-7. View

13.

Koh E, Yoon J, Ko M, Leem J, Yun J, Hong C . Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis. Gut. 2020; 70(10):1954-1964. PMC: 8458090. DOI: 10.1136/gutjnl-2020-322509. View

14.

Carvalho D, Dupuy C . Thyroid hormone biosynthesis and release. Mol Cell Endocrinol. 2017; 458:6-15. DOI: 10.1016/j.mce.2017.01.038. View

15.

Leppanen T, Tuominen R, Moilanen E . Protein kinase C and its inhibitors in the regulation of inflammation: inducible nitric oxide synthase as an example. Basic Clin Pharmacol Toxicol. 2013; 114(1):37-43. DOI: 10.1111/bcpt.12139. View

16.

Peng W, Logan C, Fish M, Anbarchian T, Aguisanda F, Alvarez-Varela A . Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture. Cell. 2018; 175(6):1607-1619.e15. PMC: 6497386. DOI: 10.1016/j.cell.2018.11.012. View

17.

Valdearcos M, Robblee M, Benjamin D, Nomura D, Xu A, Koliwad S . Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep. 2014; 9(6):2124-38. PMC: 4617309. DOI: 10.1016/j.celrep.2014.11.018. View

18.

Uyama N, Geerts A, Reynaert H . Neural connections between the hypothalamus and the liver. Anat Rec A Discov Mol Cell Evol Biol. 2004; 280(1):808-20. DOI: 10.1002/ar.a.20086. View

19.

Thaler J, Yi C, Schur E, Guyenet S, Hwang B, Dietrich M . Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2011; 122(1):153-62. PMC: 3248304. DOI: 10.1172/JCI59660. View

20.

Tommasini I, Cerioni L, Palomba L, Cantoni O . Prostaglandin E2 signals monocyte/macrophage survival to peroxynitrite via protein kinase A converging in bad phosphorylation with the protein kinase C alpha-dependent pathway driven by 5-hydroxyeicosatetraenoic acid. J Immunol. 2008; 181(8):5637-45. DOI: 10.4049/jimmunol.181.8.5637. View