CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

• DOI: 10.1016/j.celrep.2017.10.099
• Publication Date: 2017-11-22T14:06:35Z
• Authors: Zhao-Qing Shen; Yi-Fan Chen; Jim-Ray Chen; Yuh-Shan Jou; Pei-Chun Wu; Cheng-Heng Kao; Chih-Hao Wang; Yi-Long Huang; Chian-Feng Chen; Ting-Shuo Huang; Yu-Chiau Shyu; Shih-Feng Tsai; Lung-Sen Kao; Ting-Fen Tsai
• Keywords: nonalcoholic fatty liver disease; 0301 basic medicine; Carcinoma, Hepatocellular; QH301-705.5; Autophagy-Related Proteins; Nerve Tissue Proteins; Haploinsufficiency; Mice; 03 medical and health sciences; Non-alcoholic Fatty Liver Disease; Animals; Homeostasis; Humans; tumor suppressor gene; Biology (General); Serca2b; calcium homeostasis; Liver Neoplasms; Membrane Proteins; hepatocellular carcinoma; haploinsufficiency; 3. Good health; CISD2; Calcium; ER stress; Carrier Proteins

CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca2+ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca2+ uptake and maintains intracellular Ca2+ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.