1578-P: Recombinant Decorin Improves Features of Diabetes-Related Steatotic Liver Disease in Mice

Although type 2 diabetes closely associates with metabolic dysfunction-associated steatotic liver disease (MASLD) and accelerates its progression to steatohepatitis (MASH), fibrosis and hepatocellular carcinoma (HCC), still no treatment has been approved for MASLD. The extracellular matrix proteoglycan, decorin (DCN) may protect against fibrosis and HCC, but its role in MASLD is yet unclear.

Thus, we treated mice for 8 w with recombinant human DCN (200 μg/kg/day) or phosphate-buffered saline (PBS) via subcutaneous osmotic pumps. Diabetes-related MASH was induced by injecting two-day old male C57BL/6j mice with 200 µg streptozotocin and subsequent feeding a high-fat diet from 4 w on. Control mice (CTRL) received vehicle and standard diet. Hepatic steatosis, inflammation, ballooning, and fibrosis were quantified by histology. Liver mitochondrial respiration and mitochondrial ROS were assessed by high-resolution respirometry. Plasma metabolites and liver protein and gene expression levels were quantified by colorimetric assays, ELISA and qPCR.

MASH treated with PBS showed greater hepatic steatosis and ballooning, along with 3.28fold rise in blood glucose as compared to CTRL (p<0.01). DCN, but not PBS reversed liver steatosis in diabetic MASH (p<0.001 and p>0.05 vs CTRL). Median score of ballooning was lower with DCN than with PBS treatment (p<0.05). Compared to PBS, DCN lowered hepatic expression of genes involved in lipid synthesis, e. g. Fasn and Srebf, and increased plasma HDL-cholesterol. DCN also downregulated specific inflammation- and fibrogenesis-related genes, e. g. Il6 and Tgfβ (both p<0.05 vs PBS). DCN-treated livers showed increased fatty acid oxidation-linked mitochondrial respiration and reduced mitochondrial ROS production (p<0.001 and p<0.05 vs PBS).

In conclusion, DCN improves biomarkers of hepatic cellular injury in MASH, likely by enhancing hepatic mitochondrial capacity, and may therefore represent a promising concept for treating MASLD in diabetes.