Activation of ADRB2/PKA Signaling Pathway Facilitates Lipid Synthesis in Meibocytes, and Beta-Blocker Glaucoma Drug Impedes PKA-Induced Lipid Synthesis by Inhibiting ADRB2

• Published in: International journal of molecular sciences 2022-08, Vol.23 (16), p.9478
• Main Authors: Jun, Ikhyun, Choi, Young Joon, Kim, Bo-Rahm, Seo, Kyoung Yul, Kim, Tae-im
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Adipocytes; ADRB2; Adrenergic receptors; Agonists; Cell differentiation; Cyclic AMP response element-binding protein; Drug development; Epithelial cells; Epithelium; Eye diseases; Forskolin; Glands; Glaucoma; Immunoblotting; Kinases; Lipids; lipogenesis; meibomian gland dysfunction; Pathophysiology; Peroxisome proliferator-activated receptors; Phosphorylation; Physiology; PPARγ; Protein expression; Protein kinase A; Proteins; Receptors (physiology); Salbutamol; Signal transduction; Sterol regulatory element-binding protein; Therapeutic targets; Timolol
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23169478

Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs.