Genotype affects Individual Susceptibility to Nonalcoholic Fatty Liver Disease and Silibinin Therapeutic Response via Wnt/β-catenin-Cyp2e1 Signaling.

Nonalcoholic fatty liver disease (NAFLD) is a serious threat to human health worldwide, with a high genetic susceptibility. a functional germline variant of , has been recently found to associate with NAFLD risk. This study was aimed to clarify the underlying mechanism associated with risk and its impact on pharmacotherapy in treatment of NAFLD. Venous blood samples were collected from NAFLD and non-NAFLD patients for SNP genotyping by using mass spectrometry. The -floxdel mouse () was generated to model the partial function associated with human . The liver injury and therapeutic effects of silibinin were compared between and mice received a methionine-choline deficient (MCD) diet or normal diet. The effect of Lrp6 functional alteration on Wnt/β-catenin-Cyp2e1 signaling activities was evaluated by a series of cellular and molecular assays. The T allele of was confirmed to associate with a higher risk of NAFLD in human subjects. The carriers of had reduced level of AST and ALT as compared with the noncarriers. The mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of silibinin in comparison to the mice, suggesting Lrp6 as a target of silibinin. Wnt/β-catenin-Cyp2e1 signaling together with ROS generation could be exacerbated by the overexpression of Lrp6, while decreased in response to siRNA or silibinin treatment under NAFLD modeling. The function affects individual susceptibility to NAFLD and the therapeutic effect of silibinin through the Wnt/β-catenin-Cyp2e1 signaling pathway. The present work has provided an underlying mechanism for human individual susceptibility to NAFLD associated with polymorphisms as well as a rationale for the effective use of silibinin in NAFLD patients.