In our study, considering that hypercholesterolemia was mainly correlated with cholesterol decomposition and transportation, a systematic approach to the above relevant gene expression was focused, and we thus found that L. plantarum WLPL21 significantly upregulated the expression of decomposition genes (Cyp7a1, Cyp7b1, Cyp27a1, and Cyp8b1) (p < 0.05) in the liver, significantly upregulated that of transportation genes (Abca1, Abcg5, and Abcg8 in liver, Abcg5 and Abcg8 in ileum) (p < 0.05), or downregulated Npc1l1 expression in the ileum (p < 0.001). This evidence concerns the gene NPC1L1 and familial hypercholesterolemia.