Macrophage-specific Autotaxin Deficiency Promotes Hepatic Steatosis and Inflammation in Diet-induced MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder in which dysregulated inflammation plays a central role. We previously reported that macrophage-specific deletion of autotaxin (ATX) exacerbates inflammatory responses, including LPS-induced peritonitis and IL-10 deficiency-mediated colitis in mice. Moreover, circulating ATX levels are elevated in patients with MASLD. This study aimed to determine whether macrophage-specific ATX deficiency influences MASLD progression. To this end, MASLD was induced using amylin liver non-alcoholic steatohepatitis (AMLN) diet in macrophage-specific ATX knockout (Atx ΔME/ΔME ) and wild-type (Atx +/+ ) mice. ATX deficiency in macrophages promoted lipid droplet deposition in hepatocytes and hepatic triglyceride accumulation, thereby aggravating liver steatosis. Serum alanine aminotransferase, aspartate transaminase, and total cholesterol levels were significantly higher in Atx ΔME/ΔME AMLN mice compared to Atx +/+ AMLN mice. In addition, ATX deletion increased pro-inflammatory cytokine production in both Kupffer cells and hepatocytes. Notably, the expression of sterol regulatory element-binding transcription factor 1 ( Srebf1) and carbohydrate-responsive element-binding protein ( Chrebp) was elevated in Atx ΔME/ΔME AMLN mice. Collectively, these findings demonstrate that macrophage-specific ATX deficiency accelerates MASLD progression by enhancing inflammation and upregulating lipogenic transcription factors, leading to increased hepatic lipid accumulation.