The Role And Mechanism Of Oncogene Kras In Nonalcoholic Fatty Liver Disease And Its Transition To Hepatocellular Carcinoma

BACKGROUND & AIMSObesity is associated with increased risk for liver cancer due to the hepatic lipid metabolism disorders.The ubiquitous activation of Ras pathway has been demonstrated in human hepatocellular carcinoma(HCC).However,it is unclear about the association of Ras activation and lipid metabolic abnormality during hepatocarcinogenesis.We investigated whether the obesity induced by a high-fat diet increases Ras activity and predisposes mice with oncogenic Kras activation to accelerated abnormal lipid metabolism.METHODSHepatocyte-specific expressions of KrasG12Dmice(Alb-Cre/KrasG12D)were fed with high fat diets(HFDs).Liver tissues from mice were collected and analyzed for Ras downstream signaling,inflammation,nonalcoholic fatty liver disease(NAFLD),cancer cell stemness,and HCC incidence.A CPT1 inhibitor was administered to some mice to study the effect of Ras on fatty acid(FA)-? oxidation and liver carcinogenesis.RESULTSLiver tissues from dietary obesity-bearing wild type(wt)mice showed active Ras downstream pathways,and that from Alb-Cre/KrasG12 Dfed HFDshad further increased Kras downstream signaling pathways than Alb-Cre/KrasG12 D fed control diets.Alb-Cre/KrasG12 D fed HFDs had earlier occurrence of HCC,and more tumors than that fed control diets did.More proliferative hepatocytes,inflammation,and characteristic feature of cancer cell stemness were also observed in HFD-KrasG12 D group.Interestingly,Alb-Cre/KrasG12 D mice fed with HFDs had lesser adipose and a lesser extent of NAFLD but were accompanied with hypermetabolic rate than control group did.Moreover,HFD-krasG12 D mice presented the increased expression of CPT1?,a promoter of fatty acid oxidation,and the decreased expression of lipid synthesis molecules in the liver.Consistently,increased oxidative stress,DNA damage,and apoptosis were observed in HFD-krasG12 D group.Administration of a CPT1? inhibitor to Alb-Cre/KrasG12 D mice prevented these effects of HFDs.A significant reduction of tumor incidences and oxidative stress were also observed in Alb-Cre/KrasG12 D mice fed HFDs.CONCLUSIONSAn HFD can activate oncogenic Kras via CPT1? in mice,leading to expedited fatty acids ?-oxidation,increased oxidative stress,liver inflammation and hepatocarcinogenesis.This mechanism might be involved in the association between risk for HCC and HFDs.