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.

Keywords: CREBZF; SMILE; bZIP proteins; liver; metabolic pathways; nuclear receptors; transcription factors.

Figure 1

SMILE structure. (A). Small heterodimer partner-interacting leucine zipper (SMILE) is a bZIP transcription factor. The sequence of NLLAALL, where L represents leucine, is important in DNA binding. The lack of the N residue and the change of leucine to valine results in a conformational change that is the difference between other bZIP proteins and SMILE, where SMILE lacks the ability to bind to the DNA as a homodimer. (B). SMILE has two isoforms, a long form known as SMILE-L/CREBZF and a short isoform known as SMILE-S/Zhangfei (ZF), which are formed by the alternative initiation codon. SMILE-L/CREBZF has the N-terminus region that spans around 83 amino acids, similar to the bZIP CREBH family. The numbers indicate the amino acid number.

Figure 2

Modes of action of SMILE (A). SMILE, as a transcriptional corepressor, binds directly to DNA and inhibits target gene transcription. (B). Target gene expression is regulated by the corepressor SMILE and several coactivators competing to bind to the transcription factors. (C). SMILE recruits enzymes such as histone deacetylases (HDACs) to inhibit the transcription of target genes upon binding to the transcription factor as a complex.

Figure 3

SMILE, an inducible transcriptional corepressor. Many inducible stimuli such as insulin, curcumin, UDCA, and EGCG are known inducible factors that activate SMILE expression via the respective pathways. The endogenous inducers insulin and UDCA mediate SMILE expression via the PKB and AMPK pathways, respectively. Diet-derived curcumin induces SMILE expression via LKB1, which in turn activates AMPK signaling. EGCG, also as a diet-derived stimulus, mediates expression via FoxO1, which acts as a known transcription factor for SMILE expression. SMILE binds to the transcription factors and inhibits the target gene expression, acting as an inducible transcription factor.

Figure 4

The role of SMILE in regulating glucose metabolism. SMILE is an inducible transcription factor that binds to various transcription factors, such as FoxO1, CREBH, STAT-3, nuclear receptors, SREBP-1c, CREB, and HNF4α, which are activated by the signals of various liver metabolic pathways, including glucose, lipid, and iron. Glucose metabolism involves fasting and feeding conditions and involves the action of the hormones insulin and glucagon. These hormones regulate the metabolic signaling pathways via PkB/Akt and activate the transcription factors through phosphorylation, resulting in the regulation of gluconeogenic genes. During fasting, glucagon activates cAMP, which in turn activates the transcription factors CREB and FoxO1 via the PKA pathway. CREB, along with the binding of the coactivator CRTC-2, activates the transcription of PGC-1α, which acts as a coactivator for other transcription factors. In contrast, during feeding conditions, insulin induces SMILE via the PKB pathway and inhibits the action of CREB by competing with CRTC-2, inhibiting the action of PGC1α on other transcription factors and inhibits the transcription of gluconeogenic genes involved in glucose metabolism.

Figure 5

The role of SMILE in regulating lipid and iron metabolism- During lipid metabolism, oxysterols binding activates the transcription factor SREBP-1C via LXR activation, and the action of UDCA induces SMILE via the AMPK pathway, which inhibits the transcription of ACC and FAS (left panel). Curcumin and EGCG induce the expression of SMILE. SMILE inhibits the action of SMAD1/5/8, which are activated due to excess iron levels via BMP-6 and STAT-3 (right panel). BMP-6 and STAT-3 are activated due to inflammation and ER stress induced by CREBH. Inhibition of the transcription factors by SMILE inhibits genes responsible for hepcidin production.