The CIDE (cell death-inducing DFF45-like effector) family composed of CIDEA, CIDEB, CIDEC/FSP27 (fat-specific protein 27), has a critical role in growth of lipid droplets. Of these, CIDEB and CIDEC2/FSP27B are abundant in the liver, and the steatotic livers, respectively. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) has an important role in lipid homeostasis because liver-specific HNF4 alpha-null mice (Hnf4a(Delta Hep) mice) exhibit hepatosteatosis. We investigated whether HNF4 alpha directly regulates expression of CIDE family genes. Expression of Cideb and Fsp27b was largely decreased in Hnf4a(Delta Hep) mice, while expression of Cidea was increased. Similar results were observed only in CIDEC2, the human orthologue of the Fsp27b, in human hepatoma cell lines in which HNF4 alpha expressionwas knocked down. Conversely, overexpression of HNF4 alpha strongly induced CIDEC2 expression in hepatoma cell lines. Furthermore, HNF4 alpha transactivated Fsp27b by direct binding to an HNF4 alpha response element in the Fsp27b promoter. In addition, Fsp27b is known to be transactivated by CREBH that is regulated by HNF4 alpha, and expression of CREBH was induced by HNF4 alpha in human hepatoma cells. Co-transfection of HNF4 alpha and CREBH resulted in synergistic transactivation and induction of Fsp27b compared to that of HNF4 alpha or CREBH alone. These results suggest that HNF4 alpha, in conjunction with CREBH, plays an important role in regulation of Fsp27b expression. (C) 2020 Elsevier Inc. All rights reserved.