Xanthine Oxidase Promotes Hepatic Lipid Accumulation Through High Fat Absorption by the Small Intestine

Background & Aims:There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid meta-bolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate theunderlying mechanisms. Methods:The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examinedin Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition,mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and thelipid metabolism disorders. Results:After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk ofdeveloping MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01;p-trend <0.001). Moreover, serum XO activity was significantlyassociated with serum triglyceride levels (r = 0.68,p<0.001). We demonstrated that hepatic XO expression increased in liversamples from patients with MASLD. Using tissue-specificXdhknockin mice, we observed rapid lipid metabolism disordersunder a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excessdietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet. Conclusions:Our study clarified the association between serum XO activity levels and the development of MASLD in a largepopulation-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promoteslipid accumulation through mechanisms involving excessive fat absorption by the small intestine. Impact and implications:Using a prospective population-based cohort and various animal models, we have identified novelmechanisms by which xanthine oxidase regulates lipid metabolism. Ourfindings indicate that xanthine oxidase over-expression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipidtransportin vivo. These results could be important for the development of therapies to treat diseases associated with lipidmetabolism disorders.(c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).