Association of lipids in lipoprotein subfractions with liver fibrosis in a mouse model of metabolic dysfunction–associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) exhibits inflammation and fibrosis in addition to lipid accumulation in the liver, which may progress to cirrhosis and liver failure. This study investigated whether the serum lipoprotein subfraction reflects fibrosis severity in a MASH mouse model. Nine-week-old male A/J and C57BL6/J mice were fed a high-fat/cholesterol/cholate-based diet to induce fibrotic MASH. To generate fibrosis of varying severity, mice were fed two diets with different cholesterol concentrations (1.25% and 2.5%). After 9 weeks of feeding, serum cholesterol and triglyceride levels of each lipoprotein were comprehensively analyzed, including chylomicron, very-large low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), with 20 subclasses according to particle size. Serum levels of very-large HDL-cholesterol, very-small HDL-cholesterol, very-small HDL-triglycerides, and very-small LDL-cholesterol were significantly higher in the stage 2 fibrosis group than the stage 1 fibrosis group. Serum very-small LDL-cholesterol levels were correlated with histological severity of MASH, which reportedly increases with the progression of MASH in humans. In conclusion, the serum lipoprotein subfraction reflects liver fibrosis severity even in early phase, independent of the severity of other MASH lesions in MASH model mice. Fractionating HDL, which have been measured in clinical practice, may help establish noninvasive markers of liver fibrosis. J. Med. Invest. 72 : 375-384, August, 2025.