The Golden Liver Health Forum: Unleashing Innovation and Updates in Clinical Practice.

On October 25, 2024, gastroenterologists and hepatologists gathered at the Globe Auditorium, BGC braving the raging typhoon to listen to top experts talk about updates in clinical practice in managing liver disease. This was the second installment of a 2-day lecture series sponsored by Opella Healthcare Philippines.

The first session was entitled Shedding light on genomic, metabolic, and phenotypic effects of Essential Phospholipids on HepaRG by Prof Paola Luciani, PhD. The focus of her talk was examining essential phospholipids’ effects on hepatocytes, using human HEPA-RG cells to explore lipid droplet dynamics and oxidative stress resistance.

 

HEPA-RG Cells as a Model for Liver Disease

HEPA-RG cells, derived from human liver cells, are highly effective for studying liver function and disease, closely simulating human hepatic conditions. These cells allowed researchers to observe lipid droplet formation, size, and distribution—critical processes in understanding conditions like metabolic-dysfunction associated fatty liver disease (MAFLD).¹

Role of Essential Phospholipids in Lipid Homeostasis

The study focused on phosphatidylcholine (PC), an essential phospholipid crucial for stabilizing lipid droplets within hepatocytes. When lipid droplets expand and coalesce, they can disrupt cellular balance, contributing to liver disease. The researchers found that PC-rich phospholipids resulted in smaller, more stable lipid droplets, suggesting that these phospholipids play a significant role in managing lipid storage and reducing steatosis risks.¹

Mitigating Oxidative Stress

The study further revealed that essential phospholipids protect hepatocytes from oxidative stress—a key contributor to liver cell damage—by maintaining mitochondrial integrity. Using mitochondrial-specific probes, the researchers observed lower oxidative stress markers in phospholipid-treated cells, even in nutrient-deprived conditions. This finding supports the idea that essential phospholipids sustain cellular membranes and bolster antioxidant defenses in hepatocytes.

Genetic Insights from RNA Sequencing

RNA sequencing provided additional insights into how essential phospholipids influence gene expression. Genes related to lipid synthesis and metabolism showed increased expression, while those associated with lipid accumulation were downregulated. This gene profile aligns with observed changes in lipid droplets, highlighting essential phospholipids’ potential in promoting metabolic balance within liver cells.

The findings suggest that essential phospholipids support liver health by stabilizing lipid droplets, enhancing lipid turnover, and protecting against oxidative stress. These insights may prove valuable in developing therapies for lipid-related liver disorders. Further studies are recommended to validate these findings in primary human hepatocytes and clinical settings.¹

 

Essential Phospholipids: Mechanism of Action in Fatty Liver and its Implications for Patients and Physicians.

The second speaker, Prof Jose Sollano Jr., began by presenting the clinical spectrum of fatty liver disease, from nonalcoholic fatty liver disease (NAFLD) to the more comprehensive term metabolic-dysfunction-associated fatty liver disease (MAFLD). MAFLD signifies a progression where metabolic dysfunction fuels inflammation, fibrosis, and liver cell injury, with severe cases advancing to cirrhosis, liver failure, or even hepatocellular carcinoma (HCC).

With the liver being a primary organ for metabolic regulation, MAFLD not only jeopardizes hepatic health but also has systemic implications. The disease is tightly linked with metabolic syndrome, a constellation of conditions including insulin resistance, obesity, and hyperlipidemia. In patients with MAFLD, cardiovascular risks are elevated, with some patients experiencing arrhythmias and heart failure due to the inflammatory and metabolic toll the disease exerts on the body.²

Essential Phospholipids: Mechanisms of Action and Liver Protection

EPLs are a promising option in the therapeutic arsenal for MAFLD, providing a way to stabilize liver cells and protect against steatosis. Prof Sollano delved into the underlying biochemistry of EPL, highlighting their multifaceted actions at the cellular level. Essential phospholipids, including those high in phosphatidylcholine (PC) content, are crucial for liver health, as they reinforce hepatocyte membranes, reduce lipid peroxidation, and play a role in restoring normal cell structure. These attributes help buffer liver cells against oxidative damage, inflammation, and the pathological accumulation of lipids that characterizes MAFLD.

EPLs are primarily sourced from dietary phospholipids—such as 1,2-Dilinoleoylphosphatidylcholine (DLPC), Phosphatidylcholine (PC), and lecithin—which can enhance liver function in multiple ways. EPLs' actions include:

•                          Anti-cholestatic effects: EPLs support bile composition stabilization, helping to maintain normal bile flow, a process often disrupted in MAFLD.

•                          Membrane fluidity: By increasing cell membrane fluidity, EPLs aid in facilitating the transport of essential enzymes and receptors across hepatocyte membranes, thereby enhancing cellular function and resilience.

•                          Liver regeneration: EPLs are known to stimulate liver cell regeneration, crucial for mitigating MAFLD progression and liver repair after injury.

•                          Anti-inflammatory and anti-fibrotic properties: EPLs work against the inflammatory processes in MAFLD, inhibiting fibrosis and potentially preventing cirrhosis.

EPLs' Mode of Action in Liver Diseases: Clinical and Preclinical Evidence

Prof Sollano also explored key preclinical evidence showing EPLs’ therapeutic effects on lipid droplet (LD) stabilization and reduction, a process central to addressing MAFLD pathology in parallel to Prof Luciani’s earlier discussion. Studies on differentiated HepaRG cells, which mimic human liver cells, demonstrated EPLs' ability to manage oxidative stress and reduce the size of lipid droplets, which are triglyceride-rich organelles whose accumulation is a hallmark of MAFLD.

Preclinical findings indicated that when liver cells were treated with EPLs, the size distribution of lipid droplets shifted towards smaller, less inflammatory profiles. RNA transcriptomics further revealed that EPL treatment upregulated lipid metabolism-associated genes, such as PLIN2 and ANGPTL4, in affected cells, reflecting a more balanced lipid state and potentially curbing MAFLD's progression.

Furthermore, researchers highlighted that in EPL-treated cells, oxidative stress markers decreased, protecting liver cells from the injurious lipid peroxidation that often accompanies steatosis. ATGL enzymes, which support lipid degradation, were also more prevalent in EPL-treated cells, underscoring the potential of EPLs in managing liver lipid levels.¹

Lipid Droplets: Emerging Therapeutic Targets for MAFLD

Lipid droplets (LDs) are dynamic organelles that store triglycerides and play essential roles in lipid metabolism and cellular energy regulation. In MAFLD, the excessive accumulation of LDs distorts liver cell structure and function, triggering inflammation and progressive fibrosis. Understanding LD biology, the speakers emphasized, is crucial to developing new treatment strategies that can prevent or even reverse MAFLD.³

LDs interact intimately with the endoplasmic reticulum (ER) in hepatocytes. MAFLD-associated changes, such as increased LD size and number, compress sinusoidal spaces, reduce hepatic blood flow, and induce hypoxia, driving inflammation and fibrosis. Genetic and metabolic influences affect the protein and lipid composition of LDs, with protein families such as perilipins and FITM playing key regulatory roles. The symposium discussed these proteins as potential therapeutic targets, as they modulate LD formation, growth, and metabolism. By targeting LD dynamics, EPLs can directly impact the lipid accumulation and inflammation central to MAFLD pathogenesis.³ˉ⁵

Therapeutic Implications of EPLs in Real-World MAFLD Treatment

In clinical practice, managing MAFLD extends beyond pharmaceutical solutions, as access and cost can be limiting factors. Lifestyle modifications, including diet, exercise, and weight management, remain foundational aspects of MAFLD care, as the disease frequently coexists with diabetes, obesity, and cardiovascular disorders.⁵

Prof Sollano discussed how EPLs can complement these lifestyle interventions by reducing hepatic inflammation and fibrosis while supporting liver resilience and repair. Essential Phospholipids (EPL) have shown promising efficacy in improving liver parameters, particularly in patients with fatty liver disease and other hepatic conditions. EPL works by integrating into hepatocyte membranes, enhancing their structural integrity, and promoting cell regeneration. These phospholipids help restore liver function by reducing oxidative stress, modulating inflammatory responses, and improving lipid metabolism. Clinical studies demonstrate that EPL can lower transaminase levels (ALT and AST), reduce liver fat accumulation, and improve overall liver histology. Its role in stabilizing cell membranes and facilitating the repair of damaged liver tissue makes EPL a valuable adjunct in managing conditions such as MAFLD.⁵ˉ⁷

 

Concluding Remarks: EPLs and the Future of Fatty Liver Disease Care

The symposium concluded by emphasizing that EPLs represent a promising, accessible option in MAFLD care due to their favorable safety profile, affordability, and effectiveness in reducing liver lipid accumulation. EPLs, therefore, offer both preventative and therapeutic benefits for those with fatty liver disease, particularly given the limitations of current pharmacological options.⁷

As EPL research progresses, particularly in understanding LD biology and hepatocyte function, clinicians may gain more precise tools to slow or even reverse fatty liver disease progression. By incorporating EPLs into MAFLD treatment regimens, physicians can offer patients a practical solution that addresses both hepatic and metabolic health.

In summary, EPLs are not only foundational to liver cell structure and function but also represent a crucial therapeutic ally in the fight against fatty liver disease. The promising clinical and preclinical findings presented underscore EPLs’ role in managing MAFLD, from prevention to advanced care.