Peroxisome Dysfunction and Steatotic Liver Disease

Abstract

Peroxisomes are cellular organelles involved in multiple metabolic processes, including lipid oxidation, lipid synthesis, and the metabolism of reactive oxygen species. Peroxisomal disorders arise from defects in peroxisomal biogenesis or peroxisomal enzymes. Patients with severe peroxisomal disorders often present with a range of distinctive physical features and congenital malformations, such as neuronal migration defects, renal cysts, and bony stippling in the patellae and long bones. Liver disease has also been reported in some patients with peroxisomal biogenesis disorders, although the exact molecular mechanisms underlying its development remain unclear. Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognised as one of the most prevalent causes of chronic liver disease globally, due to its widespread incidence and potential for serious complications. This review aims to highlight the possible involvement of peroxisomal defects in the pathogenesis of MASLD.

Keywords: beta-oxidation; fatty acid oxidation; fatty acid synthesis; liver disease; metabolic dysfunction-associated steatotic liver disease; peroxisomes.

Figure 1

Peroxisomal Biogenesis in Mammalian Cells. The figure illustrates key steps involved in peroxisomal biogenesis. Peroxisomal membrane proteins (PMPs) are synthesised in the cytosol and are recognised by PEX19, which delivers them to the peroxisomal membrane by interacting with PEX3 and PEX16, mediating their insertion. Matrix proteins containing PTS1 or PTS2 signals are identified by cytosolic receptors PEX5 and PEX7, respectively, and targeted to the peroxisome. The receptor-cargo complex dock at the membrane via the PEX13–PEX14 complex, allowing cargo translocation into the matrix. After releasing the cargo, PEX5 is monoubiquitinated by the PEX2–PEX10–PEX12 complex and removed from the membrane by the PEX1–PEX6 ATPase complex, which is anchored by PEX26, allowing recycling of receptor back into the cytosol, ensuring proper peroxisome assembly and maintenance. In addition to import, peroxisome elongation and division is regulated by PEX11. Created in Bio Render. Subramaniam, V.N. (15 June 2025) https://BioRender.com/uyr6yts.

Figure 2

The role of peroxisomes in liver disease. The presence of peroxisome biogenesis dysfunction commonly impacts the liver in patients. The manifestations of liver pathology exhibit significant variability and are closely linked to the disease’s severity. The deficiency of peroxisomes results in impaired peroxisomal beta-oxidation, ROS imbalance, accumulation of glyoxylate, cholesterol and bile abnormalities, and reduction in ether lipids. Studies indicate that these irregularities may contribute to liver dysfunctions like cholestasis, hepatomegaly, steatosis, cirrhosis, and hepatocarcinoma; however, the exact mechanisms behind these occurrences remain unclear. Created in Bio Render. Subramaniam, V.N. (15 June 2025) https://BioRender.com/uyr6yts.