Abstract: Objective To explore the effect of chitosan oligosaccharide (COS) on hepatic lipid metabolism of PNPLA3 I148M transgenic mice. Methods Five-week-male PNPLA3 I148M transgenic mice were randomly divided into model group and COS group. The C57BL/6J mice with the same age were selected as control group. The COS group was treated with 200 mg/(kg·d) COS. The same volume of saline was administrated into the other two groups. After 16 weeks, the protein expression of PNPLA3 I148M in the liver of mice was detected by Western blot. The lipid accumulation of liver was observed by HE and oil red O staining. Triglyceride (TG) and total cholesterol (TC) content in livers were measured. At the same time, serum TG, TC, ALT and AST levels were determined. Results The protein expression of PNPLA3 I148M in mice livers of model group and COS group was up-regulated. HE staining showed that significant fatty degeneration was observed in livers of model group and few fat vacuoles with no obvious steatosis was found in COS group. Oil red O staining showed COS could significantly reduce the number and volume of lipid droplets in hepatocytes of transgenic mice. COS inhibited the increase of TG induced by PNPLA3 I148M gene, with significant difference (P ＜ 0.05). No significant difference was observed on hepatic TC contents among the three groups (P ＞ 0.05). At the same time, we found COS down-regulated serum TC and TG levels, but had no effects on ALT and AST levels in PNPLA3 I148M transgenic mice. Conclusions COS can alleviate lipid deposition in the liver of PNPLA3 I148M transgenic mice, providing a new method for the therapy of non-alcoholic fatty liver disease (NAFLD).