Glaucoma News: American Study Discovers That Sterol Regulatory Element Binding Proteins (SREBPs) Play A Role In Intraocular Pressure Regulation

Glaucoma News: Glaucoma is a serious eye condition that poses a significant threat to vision and quality of life. It is a major public health concern, affecting millions of people worldwide, especially the elderly population. One of the primary risk factors for glaucoma is the chronic elevation of intraocular pressure (IOP). Elevated IOP results in mechanical stress and reduced blood flow to the optic nerve, increasing the risk of glaucoma and vision loss. Therefore, understanding the mechanisms involved in IOP regulation is crucial for developing effective treatments and preventing the progression of glaucoma.


 
This Glaucoma News report covers a recent study conducted by researchers from Indiana University School of Medicine in the USA, in collaboration with Case Western Reserve University in Ohio and Johns Hopkins University School of Medicine in Florida that has shed new light on the regulation of IOP. The study focused on the role of sterol regulatory element binding proteins (SREBPs) in the trabecular meshwork (TM), a crucial component of the eye's drainage system.
The trabecular meshwork is composed of specialized cells that are responsible for regulating the outflow of aqueous humor (AH) from the eye. AH is the clear fluid produced by the ciliary body, and its drainage plays a fundamental role in maintaining IOP within a healthy range. The TM cells are contractile and mechanosensitive, meaning they can sense and respond to mechanical forces, which helps in the dynamic regulation of IOP.
 
The researchers were particularly interested in the role of lipids in modulating the contractility of TM cells. While previous studies had suggested a connection between lipids and IOP, the mechanistic details were unclear. To address this gap in knowledge, the research team embarked on a comprehensive investigation using human TM cells.
 
Their study identified the mechanosensing function of SREBPs, which are transcription factors involved in lipogenesis (the production of lipids), in TM cells. By activating and inhibiting SREBPs, the researchers were able to unravel the role of these proteins in regulating TM contractility and, subsequently, IOP.

One of the key findings of the study was that the pharmacological inhibition of SREBPs, using a compound called fatostatin, resulted in a significant reduction in IOP. This reduction was observed both in ex vivo (outside the living organism) and in vivo (inside the living organism) settings. Furthermore, fatostatin treatment led to decreased expression of genes and enzymes associated with lipogenesis, as well as a decrease in the levels of phospholipids, cholesterol, and triglycerides.
 
The study also revealed that fatostatin treatment had a substantial impact on actin polymerization machinery, the stabilization of the extracellular matrix (ECM), and the synthesis and secretion of ECM components. These findings pointed to a potential pathway through which modifying lipogenesis in the TM could play a crucial role in lowering IOP by influencing the biomechanics of the TM.
 
Chronic and sustained elevation in IOP is a known risk factor for primary open-angle glaucoma (POAG), the most common form of glaucoma. Reducing IOP is a proven method for de laying the onset and progression of POAG, making it a primary target for glaucoma management. The research team emphasized the significance of lowering IOP as a neuroprotective measure to minimize the risk of glaucoma and protect vision. In fact, a 20% decrease in IOP has been shown to significantly reduce the risk of developing glaucoma.
 
The balance between the production of AH by the ciliary body and its drainage through the TM and other structures, such as Schlemm's canal, determines IOP. Increased resistance to AH outflow, often due to changes in the TM, is a characteristic feature of glaucoma. These changes include increased tissue stiffness, ECM accumulation, and heightened cell contractility. Addressing these factors offers new therapeutic possibilities for lowering IOP.
 
One of the key insights from this study is the significant role that cellular lipids play in modulating tissue biomechanics. Lipids impact various cellular processes, including plasma membrane remodeling, signal transduction pathways, and the organization of the actin cytoskeleton and cell-ECM interactions. The study's results suggest that lipids in the TM and AH influence IOP by affecting signaling events, altering TM contractility, and modifying tissue stiffness.
 
Hyperlipidemia, characterized by high levels of lipids in the blood, has been associated with an increased risk of elevated IOP and glaucoma. Cholesterol-lowering medications known as statins have been shown to lower IOP and reduce the incidence of glaucoma. The researchers uncovered that cyclic mechanical stretch, mimicking the mechanical stress experienced by TM cells, led to changes in lipid content and the increased expression of enzymes involved in lipid biosynthesis. This provided a link between mechanical stress and lipid metabolism in the TM.
 
SREBPs, specifically SREBP1a, SREBP1c, and SREBP2, are master regulators of cellular lipogenesis. Each SREBP isoform has distinct roles in lipid biosynthesis, fatty acid synthesis, and sterol biosynthesis. The researchers found that SREBPs are expressed in the human AH outflow pathway, and their activation played a critical role in TM mechanosensing.
 
SREBPs exist as proforms bound to SREBP cleavage activating protein (SCAP) on the endoplasmic reticulum (ER) membrane. In response to low lipid levels, the SCAP-SREBP complex is transported to the Golgi apparatus, where it undergoes cleavage to release active or nuclear SREBPs (N-SREBPs). These N-SREBPs enter the nucleus and regulate the transcription of genes involved in lipid biosynthesis.

The research team demonstrated that SREBPs could actively sense and transduce mechanical signals in the TM. The activation of SREBPs resulted in increased actin-based contractility and the formation of lamellipodia, cellular structures involved in cell movement and adhesion.
 
Inhibition of SREBPs using fatostatin, both pharmacologically and molecularly, led to a significant decrease in IOP. The researchers proposed that inhibiting SREBPs takes time to produce the effect, but the effect is long-lasting. This delay is due to the need for regulation at the gene expression level, followed by changes in protein and enzyme levels, and finally, physiological changes. The impact of SREBPs on AH drainage through the TM outflow pathway was further confirmed by ex vivo experiments using porcine perfusion cultures.
 
Moreover, in vivo studies in mice with molecular inactivation of SREBPs by knocking down SCAP showed a substantial decrease in IOP. These results provided strong evidence that SREBPs play a crucial role in maintaining IOP.
One of the key functions of SREBPs is to regulate lipogenesis. Inactivation of the SCAP-SREBP pathway resulted in a significant decrease in various lipids, including phospholipids, cholesterol, and triglycerides in the TM. These findings suggested a connection between lowering lipids and reducing IOP.
 
The study also performed lipidomic analysis, revealing significant changes in multiple lipid subclasses after SREBPs inactivation with fatostatin. Some specific lipid subclasses, such as alkyl-PC and plasmenyl-PC, were significantly increased. These lipids belong to the category of ether phospholipids, known to be structural components of cell membranes. While ether phospholipids had not been studied in TM cells before, research in other cell types has indicated their role in regulating cell membrane dynamics, membrane trafficking, cell signaling, and antioxidant functions.
 
The connection between lipid levels in the TM and changes in IOP remains a topic of ongoing investigation. Some studies have associated elevated total triglyceride (TG) levels in the aqueous humor with an increased risk of ocular hypertension and glaucoma. However, the specific fatty acid (FA) composition of TGs in the TM had not been explored previously. The researchers found that the levels of TGs containing FA 14:0 decreased significantly, while TGs containing FA 16:0 and 18:0 increased under fatostatin treatment. These differences in TG subclasses in the TM suggested that various TG subclasses may have distinct properties and functions in TM biomechanics.
 
Cholesterol, another lipid of interest, was linked to changes in actin dynamics in the TM. The study uncovered that TM cholesterol played a significant role in maintaining the polymerized state of actin, the recruitment of focal adhesions, and TM membrane tension. These findings indicated that lipids, including cholesterol, played a crucial role in regulating the actin-cell adhesion complex and ECM interactions through the SCAP-SREBP pathway, ultimately affecting IOP regulation.
 
The research also explored the relationship between lipid changes and tissue stiffness. It demonstrated that SREBPs inactivation led to a reduction in actin stress fibers, resulting in the dissolution of focal adhesions and decreased cell-ECM connections. This loss of cell-ECM interactions contributed to TM relaxation and reduced ECM-based stiffness, leading to a decrease in IOP.
 
Moreover, the study identified changes in caveolar structures, specifically rosette formation, upon SREBPs activation. These structures were proposed to be involved in mechanosensing and mechanotransduction, potentially serving to mitigate mechanical stress and buffer membrane tension. The study further suggested that rate-limiting enzymes in lipid biogenic pathways, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCR), may influence ECM and fibrosis in various tissues.
 
The connection between SREBPs and the extracellular matrix (ECM) was also investigated. While it remains unclear whether SREBPs directly regulate the transcription of ECM genes, the study suggested that the negative feedback loop between SREBPs inactivation and ECM gene transcription was linked to the disengagement of the ECM. This led to a significant decrease in ECM components, such as collagen and fibronectin, in the outflow pathway. In vitro experiments in human TM cells provided further evidence of the inactivation of SREBPs, leading to a reduction in actin fibers and the retraction of focal adhesions.
 
The study concluded by highlighting the role of SREBPs in regulating the engagement of the ECM with the cell membrane, possibly through changes in cellular and membrane lipid composition. The researchers also noted marked changes in caveolar structures upon SREBPs activation, which could have implications for mechanosensing, mechanotransduction, and membrane tension buffering.
 
In summary, this groundbreaking study has illuminated a novel approach to lowering IOP by inactivating SREBPs. By reducing lipogenesis, modulating actin-based tension, and attenuating ECM accumulation in the TM, SREBPs play a crucial role in the mechanosensing and mechanotransduction processes involved in IOP regulation. Further research is needed to explore additional ways in which SREBPs regulate the actin cytoskeleton and ECM in the TM, with the ultimate goal of identifying new targets for IOP reduction and glaucoma therapy. These findings hold the promise of contributing to the development of more effective and targeted treatments for glaucoma, with the potential to improve the quality of life for millions of individuals affected by this sight-threatening condition.
 
The study findings were published in the peer reviewed FASEB Journal.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202301185R
 
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