Emerging Role of SMILE in Liver Metabolism.

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.

Oxidative Stress, Genomic Integrity, and Liver Diseases.

Excess reactive oxygen species production and free radical formation can lead to oxidative stress that can damage cells, tissues, and organs. Cellular oxidative stress is defined as the imbalance between ROS production and antioxidants. This imbalance can lead to malfunction or structure modification of major cellular molecules such as lipids, proteins, and DNAs. During oxidative stress conditions, DNA and protein structure modifications can lead to various diseases. Various antioxidant-specific gene expression and signal transduction pathways are activated during oxidative stress to maintain homeostasis and to protect organs from oxidative injury and damage. The liver is more vulnerable to oxidative conditions than other organs. Antioxidants, antioxidant-specific enzymes, and the regulation of the antioxidant responsive element (ARE) genes can act against chronic oxidative stress in the liver. ARE-mediated genes can act as the target site for averting/preventing liver diseases caused by oxidative stress. Identification of these ARE genes as markers will enable the early detection of liver diseases caused by oxidative conditions and help develop new therapeutic interventions. This literature review is focused on antioxidant-specific gene expression upon oxidative stress, the factors responsible for hepatic oxidative stress, liver response to redox signaling, oxidative stress and redox signaling in various liver diseases, and future aspects.

Rising Influence of Nanotechnology in Addressing Oxidative Stress-Related Liver Disorders.

Reactive oxygen species (ROS) play a significant role in the survival and decline of various biological systems. In liver-related metabolic disorders such as steatohepatitis, ROS can act as both a cause and a consequence. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are two distinct types of steatohepatitis. Recently, there has been growing interest in using medications that target ROS formation and reduce ROS levels as a therapeutic approach for oxidative stress-related liver disorders. Mammalian systems have developed various antioxidant defenses to protect against excessive ROS generation. These defenses modulate ROS through a series of reactions, limiting their potential impact. However, as the condition worsens, exogenous antioxidants become necessary to control ROS levels. Nanotechnology has emerged as a promising avenue, utilizing nanocomplex systems as efficient nano-antioxidants. These systems demonstrate enhanced delivery of antioxidants to the target site, minimizing leakage and improving targeting accuracy. Therefore, it is essential to explore the evolving field of nanotechnology as an effective means to lower ROS levels and establish efficient therapeutic interventions for oxidative stress-related liver disorders.