Interleukin13 Ameliorates Hepatocellular Steatosis via IL13Rα1/JNK/FOSL2 Signaling Pathway

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 interleukin13 (IL13) in obesity-associated liver disease progression.

IL13 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 IL13 depletion on lipid metabolism were examined in mice, whereas its mechanistic role in fat metabolism was studied in primary hepatocytes.

In a cohort of severely obese patients, plasma IL13 levels rose after weight loss and were positively associated with fibroblast growth factor 19 (FGF19), fibroblast growth factor 21 (FGF21), and insulin-like growth factor-1 (IGF1). IL13-deficient mice showed worsened liver triglyceride accumulation, lower polyunsaturated fatty acids, and altered expression of peroxisome proliferator-activated receptor-dependent lipid genes. Primary murine hepatocytes revealed that IL13 decreases triglyceride content through interleukin13Rα1 (IL‑13Rα1) and a c-Jun N-terminal kinase (JNK)-dependent c-JUN-FOS-like antigen 2 (FOSL2) axis, which enhances β-oxidation and ketogenesis. FOSL2 was required for maximal peroxisome proliferator-activated receptor (PPAR) activity and was upregulated in livers of patients with hepatic steatosis and steatohepatitis.

These data demonstrate that IL13 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.