Mutant IDH1 attenuates hepatic lipogenesis through PTEN dependent pathway

Abstract

Mutations in IDH1 (isocitrate dehydrogenases) such as R132H/Q/C, are frequently found in intrahepatic cholangiocarcinoma (IHCC). Mutant IDH1 proteins obtain an abnormal activity converting α-ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG), inhibiting the activity of multiple αKG-dependent dioxygenases, leading to metabolism disorder. Here, we depict a molecular network leading by mutant IDH1, that regulates hepatic lipid embolism using mouse model (KI) with IDH1 R132Q specifically knocked in liver. KI mice appear small and have notably reduced hepatic TG and FFA levels. Technically, mutant IDH1-mediated 2-HG can stabilize PTEN mRNA level probably depending on miR-32, activate Akt-SEBP1c signaling, leading to lipogenesis defect. Our study identifies a new role of oncometabolite 2-HG in inhibiting hepatic lipid metabolism.