If ezetimibe contributes to preventing the development of NAFLD i

If ezetimibe contributes to preventing the development of NAFLD in the FLS mice fed a normal diet, there should be an additional mechanism other than a lipid-lowering effect via NPC1L1 inhibition. Thus, in the current study, we examined the underlying effects of ezetimibe using the FLS mice fed a normal diet. Our present study revealed that ezetimibe, even in

the FLS mice fed a normal diet, prevented spontaneous development of NAFLD, with increased hepatic MTP protein level. We previously demonstrated that hepatic expression of MTP, a key regulator of VLDL assembly/export, was reduced in the FLS mouse and hepatic VLDL export was impaired in this model.[8] In addition, vector-mediated selleck products induction of MTP in the liver resulted in an improvement of VLDL export and liver lesions.[8] Thus, hepatic MTP level is crucial for the development of NAFLD Hedgehog antagonist in this model. Taking these findings together, the observed prevention of NAFLD by ezetimibe would be through its effect of amelioration of hepatic MTP level. Although we pointed out a potential role of hepatic MTP in NAFLD in the FLS mouse, a number of studies have indicated possible involvement of MTP

in the development of NAFLD/NASH. A genetic polymorphism in the promoter region of MTP was shown to be related to NAFLD susceptibility,[21] and the functional polymorphism −493 G/T in the MTP promoter was reported to be associated with the presence and severity of liver disease and with impaired lipoprotein metabolism in NASH.[22] medchemexpress Therefore, it is likely that the beneficial effect of ezetimibe

of preventing NAFLD with increased liver MTP level observed in the FLS mouse would also be expected in individuals with NAFLD. In the present study, ezetimibe significantly reduced NASH activity score and fibrosis score in the FLS mouse, showing favorable effects of ezetimibe on liver steatosis and fibrosis. Ezetimibe significantly decreased SCD1 gene expression in the liver, which was correlated with hepatic lipogenesis. The protein expression of nuclear SREBP-1 was also decreased and Ser372 phosphorylation of SREBP-1c was enhanced by ezetimibe, providing a clue that ezetimibe may decrease hepatic lipogenesis through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c-dependent lipogenesis.[23] The higher gene expression of LDL receptor was observed in the livers of CT compared with the livers of EZ, as previously reported,[20] probably because of selective compensatory induction of hepatic LDL receptor in response to the inhibition of cholesterol absorption by ezetimibe.

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