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Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is recognized as an extra-articular manifestation of psoriatic arthritis (PsA), suggesting a potential interaction between both pathologies. Apremilast, a phosphodiesterase (PDE4) inhibitor used in the treatment of PsA, has demonstrated positive anti-inflammatory and metabolic effects. These effects could potentially be beneficial for MASLD, though their impact on this condition remains insufficiently explored.
Objectives: 1) to develop a mouse model of MASLD induced by a high-fat high fructose high cholesterol diet (GAN diet) and characterize the disease progression; 2) to assess the impact of Apremilast treatment on reducing MASLD and 3) to determine the molecular mechanisms underlying the effects of Apremilast on the metabolic tissues.
Methods: 32 C57BL/6Jmice were used: 16 mice were placed in the control group with a standard diet (CHOW), and the other 16 were used to induce MASLD by a GAN diet for a period of 4 months. Each group was further subdivided into two subgroups of 8 mice, one treated with vehicle and the other with Apremilast (Amgen Agreement No: 5098797). The impact of the treatment on body weight, fat mass and lean mass percentage, was monitored and evaluated during the model development. Serum and metabolic tissues were collected. The levels of 92 proteins associated with inflammation, apoptosis, and glucose and lipid metabolism in these tissues and serum was analyzed using Olink® technology.
Results: MASLD mice induced through the GAN diet exhibited a significant increase in body weight, associated with an increase in fat mass but no changes in lean mass compared to control group. This weight gain was accompanied by elevated alanine aminotransferase (ALT) and insulin levels. Apremilast treatment reduced body weight in both groups, with a more pronounced effect in the MASLD mice. Although Apremilast did not affect lean mass, it significantly reduced fat mass, resulting in an overall weight loss of 3.92% in control mice and 9.02% in MASLD mice. At tissue level, Apremilast reduced the weight of metabolic organs such mesenteric adipose tissue and the liver, as well as levels of ALT, insulin, and triglycerides in MASLD mice. Additionally, the molecular characterization of serum, adipose tissue, and liver tissue effectively distinguished the MASLD group from the control group in an unsupervised manner, highlighting the metabolic tissue alterations induced by MASLD. The MASLD group exhibited significant alterations in 21 serum proteins compared to control mice, primarily associated with systemic inflammation. Additionally, notable changes were observed in 23 proteins within liver tissue, directly linked to inflammation, apoptosis, and lipid metabolism. Furthermore, 27 proteins in adipose tissue showed significant alterations, predominantly related to chemokine signalling pathways, apoptosis, lipid metabolism, and atherosclerosis. Interestingly, Apremilast treatment may reverse the systemic alterations by modulating the levels of key proteins, including TNF-α, TNFRSF-11B, CCL-2, DLK-1, GHRL, and WFIKK-2, among others. In liver tissue, Apremilast regulated proteins associated with apoptosis and fibrosis (FOXO-1, CASP-3, and S100A4) as well as inflammation (IL-1A). Similarly, in adipose tissue, Apremilast modulated the levels of proteins such as CCL-2, CCL-5, CXCL-1, CXCL-9, DDAH-1, RIOX-2, CASP-3, and PARP-1, which are predominantly involved in chemokine signalling, apoptosis, and oxidative stress.
Conclusion: 1) Apremilast demonstrated significant effects in slowing the progression of MASLD in mice, including reductions in body weight, fat mass, and the weight of metabolic organs; 2) the reduced progression of steatosis was associated with lower levels of ALT, insulin and triglycerides in MASLD mice; 3) proteomic analysis in metabolic tissues and serum revealed significant alterations in proteins related to inflammation, apoptosis, and lipid metabolism in MASLD mice compared to control mice and 4) Apremilast successfully restored the levels of key proteins involved in inflammation, apoptosis, fibrosis, and lipid metabolism in both serum, liver and adipose tissue of MASLD mice, highlighting its potential as a therapeutic option for MASLD, particularly in the context of PsA.
REFERENCES: NIL.
Acknowledgements: Supported the Ministry of Science, Innovation and Universities (PID2023-152503OB-I00) co-financed by the European Union and MRC MDU (MC_UU_0014/2).
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (