Non-alcoholic fatty liver disease (
NAFLD) is a serious global public health concern. Nevertheless, there are no specific medications for treating the associated abnormal accumulation of hepatic
lipids such as
cholesterol and
triglycerides. While seminal findings suggest a link between hepatic
cholesterol accumulation and
NAFLD progression, the molecular bases of these associations are not well understood. Here, we experimentally demonstrate that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a
cholesterol re-absorber from bile to the liver, can cause steatosis, an early stage of
NAFLD using genetically engineered L1-Tg mice characterized by hepatic expression of NPC1L1 under the control of
ApoE promoter. Contrary to wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice fed a high-fat diet became steatotic within only a few weeks. Moreover, hepatic NPC1L1-mediated steatosis was not only prevented, but completely rescued, by orally administered
ezetimibe, a well-used
lipid-lowering drug on the global market, even under high-fat diet feedings. These results indicate that hepatic NPC1L1 is an
NAFLD-exacerbating factor amendable to therapeutic intervention and would extend our understanding of the vital role of
cholesterol uptake from bile in the development of
NAFLD. Furthermore, administration of a TLR4 inhibitor also prevented the hepatic NPC1L1-mediated steatosis formation, suggesting a latent link between physiological roles of hepatic NPC1L1 and regulation of innate immune system. Our results revealed that hepatic NPC1L1 is a novel
NAFLD risk factor contributing to steatosis formation that is rescued by
ezetimibe; additionally, our findings uncover feasible opportunities for repositioning drugs to treat
NAFLD in the near future.