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 lipopolysaccharide -induced peritonitis and interleukin-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 nonalcoholic 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 with Atx^+/+ AMLN mice. In addition, ATX deletion increased proinflammatory cytokine production in both Kupffer cells and hepatocytes. Notably, the expression of sterol regulatory element-binding transcription factor 1 and carbohydrate-responsive element-binding protein 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.NEW & NOTEWORTHY This study reveals a protective role of macrophage-derived autotaxin (ATX) in liver homeostasis, demonstrating that its cell-specific deletion exacerbates hepatic steatosis, inflammation, and injury in a diet-induced metabolic dysfunction-associated steatotic liver disease model. Mechanistically, loss of ATX enhances proinflammatory cytokine production in Kupffer cells and hepatocytes, while upregulating lipogenic transcription factors, such as Srebf1 and Chrebp. These findings highlight macrophage-derived ATX as a critical regulator of hepatic lipid metabolism by restraining inflammation-driven lipogenesis.