Reviving peroxisome proliferator-activated receptors in fatty liver disease: From herbal formula to nuclear receptor targeting

Abstract

Due in large part to its intricate metabolic and inflammatory pathogenesis, metabolic dysfunction-associated fatty liver disease (MAFLD), the most common chronic liver disease in the world, still lacks a widely effective pharmacological treatment. Present mechanistic evidence that Lianhe Xiaozhi ointment (LXO), a formulation derived from traditional Chinese medicine, improves MAFLD by coordinating the activation of peroxisome proliferator-activated receptor alpha (PPARα). The authors show that LXO increases hepatic fatty acid oxidation and ketogenesis while inhibiting inflammatory signaling using an integrated systems approach that combines network pharmacology, hepatic transcriptomics, experimental models, and gut microbiota profiling. Significantly, LXO links intestinal metabolism to hepatic metabolic control by altering the gut microbiota and increasing endogenous fatty acid ligands, which further activate PPARα. In addition to repositioning PPARα as a key metabolic-immune hub, this study shows how multicomponent therapies may be able to overcome the drawbacks of single-target approaches in the treatment of MAFLD.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Peroxisome proliferator-activated receptor alpha; Fatty acid oxidation; Inflammation; Traditional Chinese medicine; Lianhe Xiaozhi ointment

Core Tip: The efficacy of single-target therapies is limited by interconnected metabolic, inflammatory, and gut-derived mechanisms driving metabolic dysfunction-associated fatty liver disease. According to the study covered in this editorial, the hepatoprotective effects of Lianhe Xiaozhi ointment are mediated through peroxisome proliferator-activated receptor alpha (PPARα), a key metabolic-immune hub. This work offers a systems-based therapeutic framework by improving hepatic fatty acid oxidation, reducing inflammatory signaling, and altering the gut microbiota to raise endogenous PPARα ligands. These results reinforce the gut microbiota-fatty acid-PPARα axis as a promising target for future metabolic dysfunction-associated fatty liver disease interventions and support physiological, multilevel activation of PPARα.

INTRODUCTION

The most common chronic liver disease in the world, metabolic dysfunction-associated fatty liver disease (MAFLD) is a central hepatic manifestation of systemic metabolic dysfunction. Despite significant progress in comprehending its pathophysiology, there are still few pharmacological treatments that are both effective and widely applicable. Insulin resistance, dysregulated lipid metabolism, persistent low-grade inflammation, and disruption of the gut-liver axis come together to cause MAFLD, which is not a single-pathway disease. The partial success of many single-target therapeutic approaches could be explained by this biological complexity[1-3].

From single-target pharmacological agonism to physiological, systems-level activation, Nie et al[4] showed that Lianhe Xiaozhi ointment (LXO), a formulation derived from traditional Chinese medicine, enhances the production of ketone bodies, suppresses inflammatory signaling, upregulates important downstream targets (carnitine palmitoyltransferase-1A, acyl-coenzyme A (CoA) oxidase 1, and 3-hydroxy-3-methylglutaryl-CoA synthase 2), and increases hepatic peroxisome proliferator-activated receptor alpha (PPARα) expression and transcriptional activity. Crucially, the lipid-lowering effects of LXO were partially reversed by pharmacological inhibition of PPARα, supporting the pathway’s causative role. This distinction is crucial for clinicians because physiological activation of PPARα, as opposed to supraphysiological agonism, may provide metabolic benefits with a better safety profile. Nie et al[4] offers timely and conceptually significant insights. The authors provide a convincing mechanistic framework that connects conventional medicine with modern metabolic biology by fusing network pharmacology, hepatic transcriptomics, in vitro and in vivo experiments, and gut microbiota analyses.

PPARα is a ligand-activated transcription factor. All PPARs, including PPARγ and PPARβ/δ, are involved in lipid and glucose metabolism, cell proliferation and differentiation, inflammation, vascular biology, and cancer[5,6]. The substantial differences in expression of the three PPARs across organs demonstrate their different physiological roles. PPARα expression is elevated in proximal renal tubular cells, cardiomyocytes, hepatocytes, and brown adipocytes. PPARβ/δ is mostly found in skeletal muscle, skin, adipose tissue, heart, liver, and inflammatory cells, whereas PPARγ is more extensively distributed. PPARs are activated by a variety of ligands, such as fatty acid (FA) metabolites. However, the majority of ligands and agonists do not seem to be that selective, in part because of the similarity of this family’s structures[7,8].

Lipid oxidation regulation is the primary function of PPARα, which was initially identified as a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. PPARα is logically linked to a number of diseases because lipid and even energy homeostasis preserves the body’s overall function. In the meantime, a number of diseases, such as MAFLD, diabetes, Alzheimer’s disease, and cardiovascular disease, also show a decrease in PPARα, highlighting the crucial role of PPARα in human diseases[9,10].

METABOLIC-IMMUNE INTERFACE, INFLAMMATION, AND NUCLEAR FACTOR KAPPA B

When dietary lipid intake is excessive, PPARα’s hepatic expression decreases because it is a nutritional sensor that allows the modification of FAs oxidation, lipogenesis, and ketone body synthesis rates in response to feeding and fasting. Beta-oxidases, such as carnitine palmitoyltransferase 1, a crucial enzyme in lipolysis, were upregulated following PPARα/ retinoid X receptor dimerization and entry into the nucleus, allowing FAs to migrate to the mitochondrial matrix for additional metabolism[11,12]. Additionally, PPARα increased the expression of FAs binding protein 1, or FA binding protein, which prevented hematopoietic stem cells activation and improved metabolic associated steatohepatitis (MASH)[13,14]. Mice with PPAR deficiencies in either the entire body or just the hepatocytes gained weight and developed steatosis when genes related to lipid synthesis were overexpressed, and both control and high-fat diets increased inflammation[15,16].

The mechanisms of PPARα-mediated gene suppression may be important in aggravating hepatic inflammation because PPARα represses the major pro-inflammatory transcriptional regulators, nuclear factor kappa B (NF-κB) and activator protein-1 pathways[17,18]. The study shows that LXO suppresses Toll-like receptor 4/NF-κB signaling and dramatically lowers hepatic interleukin 1 beta (IL-1β) and IL-18 levels. Because IL-1β-driven inflammation causes hepatocyte damage, cell death, and fibrogenesis, these findings are clinically significant[4]. PPARα inhibits NF-κB-mediated transcription, establishing a mechanistic connection between inflammation control and metabolic regulation[19,20]. According to the authors’ data, LXO-mediated PPARα activation supports the idea that targeting metabolic-immune crosstalk rather than isolated pathways is necessary for effective treatment of MAFLD[4].

Although currently there is lack of functional microbiome data and causal validation, the incorporation of gut microbiota analysis into the mechanistic framework is one of the study’s most intriguing features. LXO corrected the Firmicutes/Bacteroidetes imbalance, increased the abundance of several taxa linked to metabolic health, and partially restored gut microbial diversity. The enrichment of Parabacteroides distasonis, a species that has been demonstrated to reduce MAFLD by generating FA metabolites that activate PPARα, is particularly noteworthy[2]. By suppressing the T helper 1 (Th1)/Th17 inflammatory response, PPARα activity is essential for intestinal barrier integrity and the development of tolerance towards gut bacteria[21,22]. Because the Th1/Th17 response was up-regulated in the mouse model, colitis developed more easily when PPARα was absent and dysbiosis resulted[23,24]. IL-22 production in innate immune cells is upregulated by PPARα, promoting intestinal mucosa function and gut microbiota tolerance[25-27]. Figure 1 shows how LXO modulates MAFLD through PPARα-centered pathways in experimental models.

Figure 1 Lianhe Xiaozhi ointment modulates metabolic dysfunction-associated fatty liver disease through peroxisome proliferator-activated receptor alpha-centered pathways in experimental models. All mechanisms shown are preclinical and require translational validation. ACOX1: Acyl-CoA oxidase 1; AMPK: Adenosine 5’-monophosphate-activated protein kinase; BAs: Bile acids; CPT1A: Carnitine palmitoyltransferase-1A; FA: Fatty acid; FXR: Farnesoid X receptor; GLP-1: Glucagon-like peptide-1; HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2; IL: Interleukin; LPS: Lipopolysaccharide; NF-κB: Nuclear factor kappa B; PPARα: Peroxisome proliferator-activated receptor alpha; SCFAs: Short-chain fatty acids; SREBP: Sterol regulatory element-binding protein; TLR4: Toll-like receptor 4.

NATURAL PRODUCTS AND PPARΑ

In MAFLD mice, The traditional Chinese herb Scutellaria baicalensis contains a naturally occurring flavonoid called wogonin, which has been demonstrated to lower insulin resistance, hyperglycemia, and weight gain[28-30]. Additionally, β-oxidation decreases hepatic lipid buildup by triggering PPARα and adenosine 5’-monophosphate-activated protein kinase (AMPK)[31-33].

Similarly, salidroside improved MAFLD by increasing the expression of PPARα in the liver and activating peripheral and liver AMPK[34,35]. Through a PPARα-dependent mechanism, the natural antioxidant resveratrol improves oxidative stress and decreases hepatocyte steatosis[36]. Rosa roxburghii Tratt seed oil is high in unsaturated FAs and has been shown to improve mitochondrial function and promote FA oxidation through the PPARα/peroxisome proliferator-activated receptor gamma coactivator-1 alpha pathway[37,38]. Furthermore, a variety of natural substances can target PPARα and help treat MAFLD, including betanin, ursolic acid, and chicory (Cichorium intybus L.) seed extract[39,40]. By controlling PPARα and its target genes linked to hepatic lipid metabolism and gluconeogenesis, biochanin A, a naturally occurring isoflavone frequently found in legumes, can ameliorate high-fat diet-induced metabolic disorders[41,42].

Although traditional Chinese medicine has long been used empirically to treat liver and metabolic disorders, mechanistic ambiguity has prevented its integration into international hepatology[43-48]. The study by Nie et al[4] serves as an example of how contemporary multi-omics techniques can break down intricate herbal formulations into distinct biological pathways. Despite its strengths, several limitations merit discussion. The study lacks direct validation in PPARα knockout systems and mainly uses animal and cellular models. Gut microbiota analyses mostly concentrate on compositional rather than functional outputs, and the bioavailability and pharmacokinetics of LXO’s active components in humans are still unknown.

In a recent meta-analysis of 112 randomized controlled trials (10573 non-alcoholic steatohepatitis participants). Eleven traditional Chinese medicine products eight in China, two in Iran, and one in Japan have been authorized for the treatment of MASH. The most prevalent drug pair in the herbs network analysis was “Salviae Miltiorrhizae Radix Et Rhizoma + Bupleuri Radix/Alismatis Rhizoma.” Herbal remedies for MASH are increasingly using “Bupleuri Radix/Alismatis Rhizoma + Atractylodis Macrocephalae Rhizoma[49-55].” The population, intervention, comparator, outcomes, and study design of the included studies varied. Nevertheless, some studies reported inconsistent findings and neglected to provide adequate patient data, inclusion or exclusion criteria, or diagnostic standards[56].

CLINICAL IMPLICATIONS

Nie et al's findings[4] have significant clinical ramifications for the developing treatment of MAFLD. First, this study supports PPARα as a therapeutic target that is clinically relevant, especially for patients with early MAFLD who have metabolic inflammation, insulin resistance, and dyslipidemia. Second, the improvement in lipid metabolism, inflammatory markers, glucose tolerance, and liver injury that has been shown emphasizes the importance of integrated metabolic endpoints, which closely correspond with practical clinical objectives that go beyond histological steatosis alone[57,58]. Third, the idea that microbiome-targeted therapies could improve hepatic metabolic flexibility and inflammatory control in MAFLD is supported by the discovery of a gut microbiota-FA-PPARα axis. This is especially important since new treatments are beginning to identify the gut-liver axis as a modifiable cause of disease progression[59,60]. Lastly, a translational blueprint for systems-based and combination approaches that supplement incretin-based and nuclear receptor-targeted therapies presently undergoing clinical research is provided by the mechanistic dissection of a conventional formulation. When taken as a whole, these revelations support a move towards multifaceted treatment approaches that more accurately capture the biological complexity of MAFLD.

Using traditional Chinese prescriptions or drug pairs could serve as a foundation for creating new medications for the treatment of MASH. To improve the clinical trial design and gather more solid proof for the use of traditional Chinese medicines to treat MASH, more research is required.

CONCLUSION

Together, Nie et al[4] offer a convincing preclinical mechanistic framework that positions PPARα as a critical metabolic-immune node through which LXO mitigates important MAFLD characteristics. The study contributes to our understanding of how multi-component medicines may interact with metabolic regulation at the systems level instead of discrete targets. Crucially, these results should be interpreted in the context of primarily animal and cellular evidence. Clinical extrapolation is still early, despite the results supporting PPARα-centered metabolic-immune interaction as a viable therapeutic approach. However, our work supports additional research into systems-based and combination approaches for MAFLD that more accurately reflect the biological complexity of the disease and provides a useful template for creating hypotheses for future translational studies.