IL-13 ameliorates hepatocellular steatosis via IL-13Rα1/JNK/FOSL2 signaling pathway

/Aims Severe obesity is a major global health challenge and a key driver of hepatic steatosis through systemic insulin resistance and enhanced de novo lipogenesis. Excessive hepatic triglyceride accumulation represents a central metabolic consequence of this condition. This study aimed to identify immune-derived regulators of liver lipid metabolism and to define the mechanistic role of interleukin-13 (IL-13) in obesity-associated liver disease progression.

IL-13 levels and related signaling pathways were analyzed in plasma samples from patients with ≥class II obesity and liver biopsies from patients with hepatic steatosis and steatohepatitis. The effects of IL-13 depletion on lipid metabolism were examined in mice, while its mechanistic role in fat metabolism was studied in primary hepatocytes.

In a cohort of severely obese patients, plasma IL-13 levels rose after weight loss and positively associated with FGF19, FGF21, and IGF-1. IL-13-deficient mice showed worsened liver triglyceride accumulation, lower polyunsaturated fatty acids and altered expression of PPAR-dependent lipid genes. Primary murine hepatocytes revealed that IL-13 decreases triglyceride content through IL-13Rα1 and a JNK-dependent c-JUN/FOSL2 axis, which enhances β-oxidation and ketogenesis. FOSL2 was required for maximal PPAR activity and was upregulated in livers of patients with hepatic steatosis and steatohepatitis.

These data demonstrate that IL-13 is a critical immunometabolic regulator of hepatic lipid homeostasis. Targeting the IL-13-FOSL2-PPAR signaling pathway may offer a novel therapeutic approach to reduce hepatic steatosis.