Elafibranor: A promising treatment for alcohol-associated liver disease?

Abstract

We comment on an article by Koizumi et al. Elafibranor (EFN) is a dual pero-xisome proliferator-activated receptor α/δ agonist. The experimental results from Koizumi et al demonstrated that EFN significantly increases intestinal barrier function and ameliorates liver fibrosis. These positive outcomes suggest that EFN could be a promising therapeutic option for alcohol-associated liver disease (ALD). However, this study has limitations that necessitate further research to evaluate the efficacy of EFN. Future studies should consider the use of more appropriate animal models and cell types, optimize the administration routes and dosages of the drug, and conduct an in-depth investigation into the underlying mechanisms of action to determine the therapeutic effects of EFN in humans. With sustained and in-depth research, EFN has the potential to emerge as a novel therapeutic agent for the treatment of ALD.

Key Words: Alcohol-associated liver disease; Liver fibrosis; Gut barrier function; Peroxisome proliferator activated receptor; Ethanol

Core Tip: This article discusses the article by Koizumi et al on the effects of elafibranor (EFN) in treating alcohol-associated liver disease (ALD) in a mouse model. These findings are remarkable and reveal that EFN can significantly increase intestinal barrier function and ameliorate liver fibrosis. Given that the efficacy and safety of EFN have been established in patients with primary biliary cholangitis, it has emerged as an exceedingly promising candidate novel treatment modality for ALD.

TO THE EDITOR

Alcohol-associated liver disease (ALD) is one of the most common liver diseases in the world, affecting approximately 3.5% of the global population, and the five-year mortality rate exceeds 50%[1]. ALD includes a spectrum ranging from benign simple steatosis to advanced stages of steatohepatitis, fibrosis, cirrhosis, alcohol-related hepatitis (AH), and ultimately, hepatocellular carcinoma[2]. Among these conditions, fibrosis is a pivotal prognostic factor across both the compensated and decompensated stages of ALD[3]. Excessive alcohol consumption disrupts intestinal epithelial tight junctions, enhancing intestinal permeability and triggering profound changes in the gut microbiome, which promotes the transport of microbial products into the systemic circulation and subsequently to the liver, leading to the development of ALD[4,5]. Currently, abstinence from alcohol is the cornerstone of ALD management, with liver transplantation as a therapeutic option for severe cases, particularly AH. However, the availability of effective and safe therapeutic approaches for ALD is currently limited[6,7]. Therefore, there is an urgent need for further research into the pathogenesis of ALD and identification of therapeutic targets[8].

Elafibranor (EFN) is a dual peroxisome proliferator-activated receptor (PPAR) α/δ agonist. PPARs, which belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors, include three primary subtypes: PPARα, PPARγ, and PPARδ (alternatively designated PPARβ). PPARα is predominately expressed in the liver, heart, and brown adipose tissue, where it serves as a pivotal activator of the fatty acid oxidation pathway and a prime target for lipid-modulating therapeutics[9]. PPARδ, similar to PPARα in its functional repertoire, is predominately expressed in pivotal metabolic tissues, notably skeletal muscle, liver, and heart. In these tissues, it plays a pivotal role in facilitating fatty acid oxidation, thereby controlling energy metabolism, cell survival/differentiation, and inflammatory responses[10]. PPARs, which are particularly abundant in the liver, are intimately involved in a broad spectrum of physiological and pathological processes, including hepatic energy metabolism, oxidative stress, and inflammation, and are strongly associated with the progression of liver diseases[11]. Given the crucial role of PPARs in liver metabolism and inflammation, EFN, a dual PPARα/δ agonist, has therapeutic potential for the management of ALD.

Research has shown that EFN can alleviate ovalbumin-induced allergic asthma in rodent models[12], whereas a novel synthetic PPARα/δ agonist has demonstrated marked nephroprotective effects in diabetic nephropathy[13]. Current research predominantly relies on in vitro experiments and animal models, with little validation of the therapeutic efficacy and safety of EFN in human subjects in large clinical trials. Moreover, while studies have examined the impact of drug dosage on efficacy, determining the optimal dosage requires further investigation. Although preliminary insights into the mechanisms of action of EFN have been gained, a more thorough exploration of its detailed molecular mechanisms is warranted.

With respect to the clinical application of EFN, a pivotal phase III clinical trial for the treatment of primary biliary cholangitis (PBC) has yielded positive outcomes in both efficacy and safety[14], leading to its FDA approval for PBC therapy. Recently, the therapeutic potential of EFN in nonalcoholic steatohepatitis (NASH) has attracted considerable attention, with several studies indicating its ability to modulate liver fibrosis and significantly mitigate liver enzymes, blood lipids, glycemic parameters, and systemic inflammatory markers[15]. Nevertheless, in the context of human trials aimed at treating NASH, the predefined primary endpoint has yet to be achieved, prompting the termination of a phase III clinical trial owing to unmet expectations.

Notably, investigations exploring the role of EFN in ALD are limited. However, the experimental findings presented by Koizumi et al[16] suggest that EFN could emerge as a promising therapeutic option for ALD, potentially paving the way for its development as a novel drug in this field.

BASIC RESEARCH ON EFN: IMPROVEMENT OF ALD

Koizumi et al[16] described the effects of EFN on the liver and intestinal barrier of ALD model mice by conducting in vivo experiments on ethanol (EtOH) + CCL4-induced model mice and conducting a correlation analysis.

In vivo experimental findings

EFN in ALD model mice demonstrated a hepatoprotective effect by reducing steatohepatitis and lipid accumulation and increasing lipolysis and fatty acid oxidation. EFN decreased hepatocyte apoptosis, promoted proliferation, and mitigated inflammation, while restoring autophagy and reducing oxidative stress. EFN exerted an anti-inflammatory effect via inhibition of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway as well as an antifibrotic effect, thereby improving ALD prognosis. In terms of gut health, EFN preserved tight junction proteins, reduced intestinal apoptosis, and improved permeability, reinforcing intestinal integrity.

While these multifaceted benefits highlight the potential of EFN to be used as an ALD therapeutic, it is important to acknowledge the experimental limitations. Mouse models may not fully represent human ALD, and a treatment duration of 8 weeks might not be sufficient to observe the potential long-term effects of therapy. This study used two doses of EFN, and further clinical research may be necessary to determine the optimal dosage. Additionally, ALD patients often have comorbidities that could influence treatment efficacy. Future research should consider these factors and further studies should be conducted to refine our understanding of the therapeutic potential of EFN in the context of ALD.

In vitro cell experimental findings

The in vitro studies by Koizumi et al[16] confirmed the protective effects of EFN on the human hepatocellular cell line HepG2 after exposure to ethanol, and EFN reduced steatosis and apoptosis via the activation of PPARα. This research further revealed the ability of EFN to increase autophagy and the generation of antioxidant markers in HepG2 cells. Additionally, EFN was found to alleviate EtOH-induced apoptosis and permeability in the human intestinal epithelial cell line Caco-2, mainly via PPARδ activation.

While the study yielded positive results, there are inherent limitations to consider. The commonly used HepG2 and Caco-2 cell lines, although important in research, may not fully represent the physiological characteristics of normal cells, as they are cancerous in nature. Moreover, in vitro experiments are typically conducted in a controlled artificial environment, which restricts their ability to mimic the complexity of the in vivo milieu. To address these limitations, future research could use primary cells to increase the physiological relevance of the model, use three-dimensional cell culture techniques to simulate the in vivo cellular environment more accurately, and apply organ-on-a-chip technology to replicate the interactions between multiple organs and the overall response of the biological system.

Recent relevant research highlights

In a study by Hakeem et al[17], the authors used a novel combined model including both dietary NASH and chronic colitis. The findings revealed that EFN not only mitigated liver cell steatosis and lipid accumulation but also effectively suppressed the proinflammatory lipopolysaccharide (LPS) and TLR4/NF-κB signaling axes. Furthermore, this therapeutic intervention restored the normal expression of tight junction proteins in the ileum[17]. A limitation of this study is that the outcomes were obtained at a single time point, whereas inflammatory damage and other pathologies in liver diseases progress and evolve over time, so use of a single time point precluded investigations of the dynamic changes in the effects of EFN. Despite the differences in pathogenesis and pathophysiology between NASH and ALD, both involve inflammation and injury of the liver as well as intestinal barrier dysfunction. Thus, the mechanism of action of EFN identified in this study may confer benefits on ALD as well, which needs to be verified in ALD models.

In a previous and similar study, Li et al[18] examined the effects of the dual PPARα/δ agonist EFN on autophagy stimulation and its underlying mechanisms in an ethanol-induced alcoholic steatohepatitis (ASH) mouse model. The results indicated that EFN reduced the severity of liver injury by reversing the dysfunction of autophagy in adipose tissue, where autophagy had been suppressed by alcohol, and decreasing the release of apoptotic markers, inflammatory cytokines, and free fatty acids, thereby mitigating intestinal epithelial damage, hepatic inflammation, apoptosis, and steatosis in ASH mice[18]. Although the findings of this study support the potential use of EFN as a therapeutic option for ASH, providing a foundation for future clinical investigations, it has several limitations. First, the role of sex in ALD is recognized[19]; however, this study failed to address the impact of sex differences on the pathology of ASH and the efficacy of EFN treatment. Second, the focus was primarily on the early stages of ASH, and the effectiveness of EFN in treating advanced stages of ALD, such as cirrhosis, was not explored.

FUTURE DIRECTIONS AND RESEARCH

Providing more effective treatments for ALD patients is one of the most pressing needs in clinical hepatology. While the experimental results suggest that EFN is a promising treatment for ALD, there are some issues to be addressed in the application of EFN as a therapeutic agent for ALD; these issues necessitate further research.

First, chitosan-based nanoparticles that codelivered pioglitazone and curcumin significantly increased encapsulation efficiency and loading capacity compared with conventional nanoparticles. This advancement not only circumvents the inherent limitations of drugs, including low bioavailability, short half-life, and poor aqueous solubility, but also enhances their in vivo stability and delivery efficiency through optimized nanocarrier design. This approach has the potential to markedly improve the therapeutic outcomes of patients with type 2 diabetes mellitus. These findings highlight the critical role of nanocarrier selection and design in augmenting drug efficacy[20]. However, in the context of EFN, discussions surrounding its bioavailability, stability, and optimal carrier selection in vivo are lacking. Therefore, whether specific carriers are needed to guarantee the efficacy of EFN remains to be evaluated by future in-depth studies.

Second, extensive research has highlighted the ability of EFN to modulate bile acid metabolism via a multifaceted mechanism. Specifically, PPARα ligands inhibit bile acid synthesis, increase its secretion, and mitigate its toxicity, whereas PPARδ not only ameliorates hepatic steatosis and exerts anti-inflammatory effects but also contributes to regulating bile transport and absorption[21]. Given its proven efficacy and safety profile, EFN has secured clinical approval for the management of PBC[14]. However, its effect on bile acids in ALD models has not been explored. The interaction between the gut and liver is bilateral. Bile acids play a pivotal role in the pathogenesis of liver diseases, to which intestinal dysbiosis is also a significant contributor. Scientific investigations have revealed that the gut microbiota can regulate enzyme expression, thereby modulating bile acid synthesis. Conversely, bile acids can reshape the gut microbiota community by promoting the proliferation of bile acid-metabolizing bacteria and suppressing the growth of bile-sensitive species, ultimately influencing the host's metabolic state[22]. Therefore, the relationship between the effect of EFN on bile acid metabolism and its ameliorative effect on alcoholic liver injury should be further analyzed.

Third, the efficacy of EFN can vary depending on the experimental paradigm, specifically with respect to the timing of EtOH administration. Consequently, there is a need for additional investigations that use diverse ALD models to gain a more comprehensive understanding.

In conclusion, Koizumi et al[16] reported that the dual PPARα/PPARδ agonist EFN has potent inhibitory effects on hepatocyte lipid accumulation and apoptosis while enhancing autophagy and antioxidant activities in these cells. By restoring intestinal barrier function, EFN inhibits LPS/TLR4/NF-κb-mediated inflammatory responses, thereby mitigating ALD-related fibrosis. These findings highlight the significant potential of EFN for use in the treatment of ALD. Further research should more thoroughly explore the molecular mechanisms underlying the influence of EFN on the liver and intestine and compare its efficacy across various doses and routes of administration. Additionally, investigating the efficacy of EFN in combination with other drugs is crucial. Prior clinical studies on EFN in the context of PBC have validated its safety, laying a foundation for its potential use in ALD patients. However, further research in the ALD population is needed to comprehensively assess the long-term safety and tolerability of EFN. In conclusion, the findings presented by Koizumi et al[16] represent a step forward in the field of ALD treatment, and with continued research and evaluation, EFN holds immense promise as a potential therapeutic option for this condition.