In conclusion, the present study showed that in a HF diet-fed rat model, both high- and low MW chitosan (1) inhibit MTTP and increase Angptl4 protein expressions in the intestine and increase the small intestine length and fecal lipid excretion; (2) activate AMPK and inhibit downstream lipogenesis transcription factors (SREBP2, SREBP1c, and PPARγ) and protein expressions, and promote PPARα protein expression in the liver; (3) and promote liver VLDL secretion-related proteins (ApoE and MTTP) expressions, leading in reducing fatty synthesis, increasing β-oxidation, and improving fatty liver. The gene discussed is PPARG; the disease is fatty liver disease.