The role of pleckstrin homology-like domain family A member 1 in metabolic diseases

doi:10.16352/j.issn.1001-6325.2025.02.0268

Abstract

Abstract: Pleckstrin homology-like domain family A member 1 (PHLDA1) is a pro-apoptotic factor as well as a key regulator of metabolic diseases. In obesity-related diseases, PHLDA1 can reduce liver triglyceride production through inhibition of the expression of sterol regulatory-element binding proteins-1 (SREBP-1), and reduce fat synthesis through inhibition of peroxisome proliferator-activated receptor γ (PPARγ). However, in cardiovascular diseases, PHLDA1 increases vascular calcification, dysfunction, thereby aggravates ischemia-reperfusion injury in the heart and brain. The dual role of PHLDA1 has also been confirmed in tumors. In summary, PHLDA1, as a multifunctional factor, plays different functional roles through various mechanisms.

Key words: pleckstrin homology-like domain family A member 1 (PHLDA1), endoplasmic reticulum stress, obese, cardiovascular diseases

CLC Number:

HU Yanmin, PENG Lina, YANG Yong, XIANG Yunxuan, CHANG Xiaoyue. The role of pleckstrin homology-like domain family A member 1 in metabolic diseases[J]. Basic & Clinical Medicine, 2025, 45(2): 268-272.

References 23

[1]	Wu YL, Lin ZJ, Li CC, et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study[J]. Signal Transduct Target Ther, 2023,8:98. doi: 10.1038/s41392-023-01333-7.
[2]	Yousof T,Byun H J,Chen J, et al.Pleckstrin homology-like domain,family A,member 1(PHLDA1):a multifaceted cell survival factor that drives metabolic disease[J].Engineering,2023,20:9-18.
[3]	Peng H, Wang J, Song X, et al. PHLDA1 suppresses TLR4-triggered proinflammatory cytokine production by interaction with tollip[J].Front Immunol, 2022,13:731500. doi: 10.3389/fimmu.2022.731500.
[4]	Powis G, Meuillet EJ, Indarte M, et al. Pleckstrin homology[PH]domain, structure, mechanism, and contribution to human disease[J].Biomed Pharmacother, 2023,165:115024. doi: 10.1016/j.biopha.2023.115024.
[5]	Yousof TR, Bouchard CC, Alb M, et al. Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice[J].J Biol Chem, 2024,300:105655. doi: 10.1016/j.jbc.2024.105655.
[6]	Kim S, Lee N, Park ES, et al.T-Cell death associated gene 51 is a novel negative regulator of PPARγ that inhibits PPARγ-RXRα heterodimer formation in adipogenesis[J].Mol Cells, 2021,44:1-12. doi: 10.14348/molcells.2020.0143.
[7]	Wong M, Forno E, Celedón JC. Asthma interactions between obesity and other risk factors[J].Ann Allergy Asthma Immunol, 2022,129:301-306.doi: 10.1016/j.anai.2022.04.029.
[8]	Bantulà M, Arismendi E, Tubita V, et al. Effect of obesity on the expression of genes associated with severe asthma-a pilot study[J]. J Clin Med, 2023,12:4398.doi: 10.3390/jcm12134398.
[9]	Chen Z, Zhang SL. Endoplasmic reticulum stress: a key regulator of cardiovascular disease[J]. DNA Cell Biol, 2023,42:322-335. doi: 10.1089/dna.2022.0532.
[10]	Platko K, Lebeau PF, Gyulay G, et al. TDAG51 (T-cell death-associated gene 51) is a key modulator of vascular calcification and osteogenic transdifferentiation of arterial smooth muscle cells[J]. Arterioscler Thromb Vasc Biol,2020,40:1664-1679. doi: 10.1161/atvbaha.119.313779.
[11]	Liu Y, Zhao H, Chen N, et al. PHLDA1 knockdown alleviates mitochondrial dysfunction and endoplasmic reticulum stress-induced neuronal apoptosis via activating PPARγ in cerebral ischemia-reperfusion injury[J]. Brain Res Bull,2023,194:23-34. doi: 10.1016/j.brainresbull.2023.01.007.
[12]	Guo Y, Jia P, Chen Y, et al. PHLDA1 is a new therapeutic target of oxidative stress and ischemia reperfusion-induced myocardial injury[J].Life Sci, 2020,245:117347. doi: 10.1016/j.lfs.2020.117347.
[13]	Carlisle RE, Mohammed-Ali Z, Lu C, et al. TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease[J]. Cell Death Dis, 2021,12:921. doi: 10.1038/s41419-021-04197-3.
[14]	Wang X, Rao J, Chen X, et al. Identification of shared signature genes and immune microenvironment subtypes for heart failure and chronic kidney disease based on machine learning[J]. J Inflamm Res, 2024,17:1873-1895.doi: 10.2147/JIR.S450736. eCollection 2024.
[15]	Mk Nair P, Silwal K, Ramalakshmi R, et al.Beyond genetics: integrative oncology and the metabolic perspective on cancer treatment[J]. Front Oncol, 2024,14:1455022. doi: 10.3389/fonc.2024.1455022.
[16]	Xu J, Bi G, Luo Q, et al. PHLDA1 modulates the endoplasmic reticulum stress response and is required for resistance to oxidative stress-induced cell death in human ovarian cancer cells[J]. J Cancer,2021,12:5486-5493. doi: 10.7150/jca.45262.
[17]	Rahnama S, Tehrankhah ZM, Mohajerani F, et al. Milk thistle nano-micelle formulation promotes cell cycle arrest and apoptosis in hepatocellular carcinoma cells through modulating miR-155-3p /SOCS2 /PHLDA1 signaling axis[J]. BMC Complement Med Ther, 2023,23:337.doi: 10.1186/s12906-023-04168-5.
[18]	Yao B, Niu Y, Li Y, et al. High-matrix-stiffness induces promotion of hepatocellular carcinoma proliferation and suppression of apoptosis via miR-3682-3p-PHLDA1-FAS pathway[J]. J Cancer, 2020,11:6188-6203. doi: 10.7150/jca.45998.
[19]	Wang J, Yao N, Hu Y, et al. PHLDA1 promotes glioblastoma cell growth via sustaining the activation state of Ras[J]. Cell Mol Life Sci, 2022,79:520.doi: 10.1007/s00018-022-04538-1.
[20]	Iqbal S, Karim MR, Mohammad S, et al. Multiomics analysis of the PHLDA gene family in different cancers and their clinical prognostic value[J]. Curr Issues Mol Biol, 2024,46:5488-5510. doi: 10.3390/cimb46060328.
[21]	Huang R, Huang D, Wang S, et al. Repression of enhancer RNA PHLDA1 promotes tumorigenesis and progression of Ewing sarcoma via decreasing infiltrating T-lympho-cytes: a bioinformatic analysis[J]. Front Genet, 2022,13:952162.doi: 10.3389/fgene.2022.952162.
[22]	Duan Y, Du Y, Gu Z, et al. Prognostic value, immune signature, and molecular mechanisms of the PHLDA family in pancreatic adenocarcinoma[J]. Int J Mol Sci, 2022,23:10316. doi: 10.3390/ijms231810316.
[23]	Durbas M, Pabisz P, Wawak K, et al. GD2 ganglioside-binding antibody 14G2a and specific aurora A kinase inhibitor MK-5108 induce autophagy in IMR-32 neuroblastoma cells[J].Apoptosis,2018,23:492-511.doi: 10.1007/s10495-018-1472-9.