Metabolic dysfunction-associated steatotic liver disease (MASLD) typically begins with hepatic fat accumulation but can progress to steatohepatitis, fibrosis, cirrhosis, and liver cancer. IL-15 sits at the intersection of metabolism and immunity, yet previous studies have yielded inconclusive results regarding whether it exacerbates or ameliorates fatty liver disease. This study investigates whether this discrepancy stems from differences in the source of signaling, hypothesizing that the liver and intestinal epithelium may utilize the same IL-15/IL-15Rα axis in distinct ways.

The team approached the question from two directions. First, they reanalyzed human and mouse liver transcriptomes from GSE246221, using CIBERSORTx to estimate immune-cell composition. They then studied high-fat-diet-fed mice with hepatocyte-specific Il15 deletion and intestinal epithelial Il15 or Il15ra deletion. Histology, circulating lipids and liver enzymes, hepatic gene expression, and IL-15/IL-15Rα complexes were assessed.

In human liver, IL15 increased from healthy tissue through early-to-moderate MASH and then fell at later stages; in mice, Il15 peaked during fibrotic MASH. Human IL15 was modestly associated with CD86 and CD163, while mouse Il15 correlated with Cd86. Against genotype-matched controls, hepatocyte Il15 deletion reduced weight gain, steatosis, NAFLD activity score, serum triglycerides, and ALT, and increased hepatic Prkaa1 and Ppara expression; fibrosis was not detectably changed. A separate, exploratory comparison found that intestinal epithelial Il15ra knockout mice had similar steatosis but more PSR-positive fibrosis, higher AST, lower circulating IL-15/IL-15Rα complexes, higher hepatic F4/80, and lower Cd8a expression.

These findings show the importance of distinguishing hepatic and intestinal components of the IL-15 axis in MASLD. The improvement in steatosis following hepatocyte IL-15 deletion, together with the fibrosis phenotype associated with intestinal IL-15Rα deficiency, directs attention to tissue-selective rather than systemic interventions. This distinction provides a basis for investigating how to reduce hepatic metabolic injury while preserving intestinal IL-15-related functions.
Doi: 10.63823/ARP0260013