Background:
Nonalcoholic fatty liver disease (
NAFLD) is a serious threat to human health worldwide, with a high
genetic susceptibility. Rs2302685, a functional germline variant of LRP6, has been recently found to associate with
NAFLD risk. This study was aimed to clarify the underlying mechanism associated with rs2302685 risk and its impact on
pharmacotherapy in treatment of
NAFLD. Methods: Venous blood samples were collected from
NAFLD and non-
NAFLD patients for SNP genotyping by using mass spectrometry. The Lrp6-floxdel mouse (Lrp6(+/-)) was generated to model the partial function associated with human rs2302685. The liver injury and
therapeutic effects of
silibinin were compared between Lrp6(+/-) and Lrp6(+/+) 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. Results: The T allele of LRP6 rs2302685 was confirmed to associate with a higher risk of
NAFLD in human subjects. The carriers of rs2302685 had reduced level of AST and ALT as compared with the noncarriers. The Lrp6(+/-) mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of
silibinin in comparison to the Lrp6(+/+) 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 Lrp6
siRNA or
silibinin treatment under
NAFLD modeling. Conclusions: The Lrp6 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 Lrp6 polymorphisms as well as a rationale for the effective use of
silibinin in
NAFLD patients.