Interleukin‐38 alleviates hepatic steatosis through AMPK/autophagy‐mediated suppression of endoplasmic reticulum stress in obesity models

Abstract

AbstractInterleukin‐38 (IL‐38), recently recognized as a cytokine with anti‐inflammatory properties that mitigate type 2 diabetes, has been associated with indicators of insulin resistance and nonalcoholic fatty liver disease (NAFLD). This study investigated the impact of IL‐38 on hepatic lipid metabolism and endoplasmic reticulum (ER) stress. We assessed protein expression levels using Western blot analysis, while monodansylcadaverine staining was employed to detect autophagosomes in hepatocytes. Oil red O staining was utilized to examine lipid deposition. The study revealed elevated serum IL‐38 levels in high‐fat diet (HFD)‐fed mice and IL‐38 secretion from mouse keratinocytes. IL‐38 treatment attenuated lipogenic lipid accumulation and ER stress markers in hepatocytes exposed to palmitate. Furthermore, IL‐38 treatment increased AMP‐activated protein kinase (AMPK) phosphorylation and autophagy. The effects of IL‐38 on lipogenic lipid deposition and ER stress were nullified in cultured hepatocytes by suppressing AMPK through small interfering (si) RNA or 3‐methyladenine (3MA). In animal studies, IL‐38 administration mitigated hepatic steatosis by suppressing the expression of lipogenic proteins and ER stress markers while reversing AMPK phosphorylation and autophagy markers in the livers of HFD‐fed mice. Additionally, AMPK siRNA, but not 3MA, mitigated IL‐38‐enhanced fatty acid oxidation in hepatocytes. In summary, IL‐38 alleviates hepatic steatosis through AMPK/autophagy signaling‐dependent attenuation of ER stress and enhancement of fatty acid oxidation via the AMPK pathway, suggesting a therapeutic strategy for treating NAFLD.