IDH1 Mutants-induced Metabolic Alterations Of Glucose And Lipid And Their Possible Contribution To Tumorigenesis

Isocitrate dehydrogenases1(IDH1)catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate(α-KG).In recent years,various mutants of IDH1 Arg132 have been found to produce high level of 2-hydroxyglutarate(2-HG),an oncometabolite,which in turn promotes the generation of a variety of malignant tumors such as gliomas,acute myeloid leukemia(AML)and hepatocellular carcinoma.Mechanistically,2-HG has been considered to competitively inhibit α-KG dependent dioxygenases and thus increases the expression of HIF-1α,the methylation levels of genome-wide DNA and/or histone,leading to the block in cellular differentiation and tumorigenesis.It has been well understood that metabolic remodeling of glucose and lipid plays important role in tumorigenesis.However,there is a lack of comprehensive studies on the disorder of glucose and lipid metabolism induced by IDH1 mutants and its role in tumorigenesis with an appropriate mice model until now.Since liver is the center organ of mammalian glucose and lipid metabolism,in our research,we generated liver-specific IDH1 R132Q knock-in(Alb-KI)mice and preliminarily investigated the metabolic alterations of glucose and lipid induced by IDH1 mutants.We found that Alb-KI mice are significantly smaller in body size,and have statistically significant lower body weights than Alb-WT mice.The livers of Alb-KI mice produce large amounts of 2-HG and are accompanied with the formation of spontaneous hepatocellular carcinoma.As a result,the life span of Alb-KI mice is dramatically shortened.The metabolic patterns of Alb-KI mice are significantly changed:(1)The Alb-KI mice show a metabolic pattern of higher energy expenditure feature by significantly enhanced food intake and catabolism.This metabolic alteration may attribute to the production and excretion of a large amount of 2-HG,a five-carbon metabolic end product,derived from other carbon sources such as glucose and lipid.(2)The glucose metabolism is significantly altered in Alb-KI mice liver.The glycolysis and lactate production are significantly enhanced,consistently,the expression of key enzymes of glycolysis are upregulated.The blood glucose concentration is decreased due to the accelerated consumption of glucose.(3)α-KGDH in the TCA cycle is inhibited by 2-HG and the potential of oxidative phosphorylation is impaired.(4)The body fat content of Alb-KI mice is decreased and the de novo lipogenesis from glucose is suppressed.However,the fatty acid β-oxidation is enhanced along with the remarkable upregulation of CPT1A,the rate-limiting enzyme in fatty acid β-oxidationThe above metabolic changes are verified in HT1080 tumor cells carrying natural IDH1 mutant and liver cancer cells overexpressing IDH1 mutant.Furthermore,we observed that the enhancement of catabolism of fatty acids in mutant cells is particularly important for cell survival and proliferation due to reasons:on the one hand such alteration can provide energy,but more importantly it can generate more NADPH through IDH2 catalyzed dehydrogenation for scavenging already increased ROS level in mutant cells.Consistently,inhibition of CPT1A can significantly inhibit the survival and proliferation of IDH1 mutant cells,indicating that this metabolic change may play an important role in tumorigenesis driven by IDH1 mutants.In summary,we reveal the metabolic alterations of glucose and lipid induced by IDH1 mutants,and explore their possible contribution to tumorigenesis by creating Alb-KI mice.Furthermore,the investigation of metabolic alterations of glucose and lipid provides a potential target for the treatment of tumors induced by IDH1 mutants.