Emerging Role of SMILE in Liver Metabolism

Abstract

Small heterodimer partner-interacting leucine zipper (SMILE) is a member of the CREB/ATF family of basic leucine zipper (bZIP) transcription factors. SMILE has two isoforms, a small and long isoform, resulting from alternative usage of the initiation codon. Interestingly, although SMILE can homodimerize similar to other bZIP proteins, it cannot bind to DNA. As a result, SMILE acts as a co-repressor in nuclear receptor signaling and other transcription factors through its DNA binding inhibition, coactivator competition, and direct repression, thereby regulating the expression of target genes. Therefore, the knockdown of SMILE increases the transactivation of transcription factors. Recent findings suggest that SMILE is an important regulator of metabolic signals and pathways by causing changes in glucose, lipid, and iron metabolism in the liver. The regulation of SMILE plays an important role in pathological conditions such as hepatitis, diabetes, fatty liver disease, and controlling the energy metabolism in the liver. This review focuses on the role of SMILE and its repressive actions on the transcriptional activity of nuclear receptors and bZIP transcription factors and its effects on liver metabolism. Understanding the importance of SMILE in liver metabolism and signaling pathways paves the way to utilize SMILE as a target in treating liver diseases.

Androgen synthesis cell‐specific CREBZF deficiency alters adrenal cortex steroid secretion and develops behavioral abnormalities in adult male mice

“…However, due to conformational changes caused by a lack of an Asn residue in N‐terminus, CREBZF has to exert transcriptional regulation by heterodimerization 23,26,27 . Based on the above characteristics, several additional studies have shown that CREBZF is widely involved in physiological processes such as metabolism, 28–32 cancers, 33–37 apoptosis, 38–40 autophagy, 41 and unfolded protein response (UPR) 42–45 . In recent years, we 40,46,47 and others 48–50 have validated the expression pattern of CREBZF in the gonads, indicating that CREBZF plays important roles in gametogenesis, embryo implantation, and steroid hormonal regulation.…”

“…However, due to conformational changes caused by a lack of an Asn residue in N-terminus, CREBZF has to exert transcriptional regulation by heterodimerization. 23,26,27 Based on the above characteristics, several additional studies have shown that CREBZF is widely involved in physiological processes such as metabolism, [28][29][30][31][32] cancers, [33][34][35][36][37] apoptosis, [38][39][40] autophagy, 41 and unfolded protein response (UPR). [42][43][44][45] In recent years, we 40,46,47 and others [48][49][50] have validated the…”