Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe‐mediated steatosis prevention and recovery

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.