| Non-alcoholic fatty liver disease(NAFLD),characterized by ectopic accumulation of triglycerides(TG)in hepatocytes,has emerged as one of the most prevalent chronic liver disease in the past few decades.Obesity is the leading risk factor for NAFLD,as it associated with enhanced import or synthesis of TG and reduced TG export or FFA catabolism.The simple steatosis can be reversed,therefore,investigating the molecular mechanisms of obesity-induced hepatic steatosis would help identify therapeutic intervention targets for NAFLD.Farnesyl diphosphate(FPP)and geranylgeranyl diphosphate(GGPP)are important intermediates of mevalonate pathway,which function in proteins prenylation,including farnesylation and geranylgeranylation.Interestingly,FPP and its derivant farnesol(FOH)are reported to suppress TG synthesis through down-regulating of de novo lipogenesis(DNL)and enhancing β-oxidation.Additionally,squalene synthase inhibitors suppress cholesterol synthesis and lead to amounts of FPP and FOH accumulation,which also inhibit TG biosynthesis.Here,we hypothesize that FPP and FOH may play essential roles in negatively regulating hepatic lipid anabolism.Approaches tend to increase the FPP and FOH levels might improve hepatic lipid disorder.Geranylgeranyl diphosphate synthase(GGPPS)catalyzes the synthesis of GGPP from its substrate FPP.We have previously proved that specific inactivation of GGPPS altered FPP/GGPP ratio and resulted in FPP accumulation.In this research,we focused on 1.Whether GGPPS controlled FPP level is involved in regulating hepatic lipid metabolism?2.How accumulated FPP negatively regulates hepatic lipid accumulation?3.Whether approaches,such as specific targeting GGPPS and increase FPP level could improve the lipid disorder?In this study,we found GGPPS is up-regulated in the liver of obesity-associated hepatic steatosis mice models,as in the ob/ob obese mice,db/db diabetic mice and high-fat diet-fed hepatic steatotic mice.Meanwhile,hepatocytes over-expression of GGPPS exhibited prone to accumulate TG,while silencing of GGPPS by siRNA attenuated FFAs-induced TG deposition.This is consistent with the GGPPS-null hepatocytes isolated from GGPPS knockout mice which displayed resistance to FFAs-induced steatosis as well.Last but importantly,specific ablation of GGPPS in liver prevented mice from high-fat diet-induced hepatic steatosis.These results suggested that GGPPS was involved in promoting hepatic lipid deposition.Further investigation revealed that GGPPS modulated hepatic TG metabolism through enhancing fatty acid synthesis while suppressing the TG clearance.For the mechanism exploration,we proved that deletion of GGPPS increased the FPP/GGPP ratio and led to the accumulation of FPP and FOH.The increased FPP level,on one hand,promoted LKB-1 farnesylation,which shutting off the fatty acid synthesis through activating AMPK.On the other hand,the accumulated FPP and FOH also functioned in activating FXR/SHP signaling thus suppressed SREBP-1c maturation and downstream lipogenic genes expression.We proved that specific targeting GGPPS altered FPP/GGPP ratio,thus improved the hepatic lipid accumulation.Herein,we down-regulated GGPPS activity through administrating DGBP,a proved GGPPS inhibitor in vitro or silencing GGPPS with siRNA in vivo,which both attenuated hepatic lipid accumulation towards the HFD feeding.The clinical drug,zoledronate was reported to alter the FPP/GGPP ratio,which was also applied in our study.Above all,we proved that zoledronate improved lipid disorder in HFD-induced hepatic steatosis mice and ob/ob mice.Taken together,our study proved that GGPPS played a vital role in regulating lipid homeostasis through tilting the FPP/GGPP ratio.Thus,specific targeting GGPPS mediated alteration of FPP/GGPP ratio provides a new therapeutic strategy to combat obesity-associated hepatic steatosis. |
