Absent in Melanoma (AIM) 2, an HIN-200 domain family interferon inducible gene, is a cytosolic sensor for double-stranded DNA, forms the AIM2 inflammasome, and is a tumor suppressor gene. Lack of AIM2 increases the risk for cancers including liver cancer. We had earlier shown that mice with whole body deletion of AIM2 (AIM2-/-) exhibit increased body weight and total fat mass (without change in lean mass), visceral and subcutaneous adiposity, elevated fasting glucose and impaired glucose tolerant test without significant change in food intake. To assess the effects of AIM2-/- on liver, we analyzed liver weight, gene expression and protein levels of key players of hepatic lipid metabolism in female wild type (WT) and AIM2-/- mice (14-month-old, n=7/group) on chow diet. Fatty acid oxidation in liver was determined by incubating 14C-palmitate with liver lysate, and trapping and quantifying the 14CO2 generated from the 14C-palmitate. We found that liver was enlarged in AIM2-/- mice compared to WT controls (liver weight 1.25±0.03 vs. 1.62±0.09 g, p<0.01 and liver/body weight 0.037±0.001 vs. 0.042±0.002 in WT and AIM2-/- respectively, p=0.02). Histological examination demonstrated significantly increased lipid deposition in the liver of AIM2-/- mice. Expression levels of lipogenic genes, such as ACC1 (4 fold), ACC2 (3.2 fold), PPARγ (2.8 fold), C/EBPα (2.4 fold), CD36 (2.4 fold), Fasn (4.3 fold) and SREBP-1c (3.8 fold) were significantly increased in AIM2-/- mice; increases in lipogenic gene expression in the liver are likely due to the phosphorylation and nuclear localization of STAT3. Fatty acid oxidation was not affected in liver of AIM2-/- mice (22.8±2.4 vs. 25±3.9 pmoles/ug/hr, p=0.52). Taken together, our data provides strong evidence that AIM2 is a regulator of hepatic fat, thereby providing a novel target for treatment of NALFD. AIM2 is a novel link between innate immunity, cancer and obesity.


Z. Gong: None. R. Jiang: None. K. Su: None. E. Goetzman: None. H. Dong: None. R. Muzumdar: None.

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