Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system’s components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

“…Moreover, mitochondrial dysfunction and associated oxidative stress are the hallmark feature of NAFLD and NASH development [22]. Mitochondrial stress promotes cell death, liver fibrogenesis, inflammation, and innate immune responses, such as the accumulation of mitochondrial DNA (mtDNA) leading to enhanced production of inflammatory cytokines, e.g., interferons (IFNs) that are responsible for the development and progression of NAFLD as reviewed elsewhere [23,24] Accumulating evidence also suggests the circadian clock (mammalian ≈24-h endogenous timing mechanism) as a major regulator of critical physiological functions, including hepatic metabolic processes, such as glucose, lipid, or cholesterol/bile acids metabolism [25]. Disruption of the circadian clock has been shown to play an important role in increasing the incidence of metabolic dysregulation, significantly contributing to the development of metabolic syndrome and NAFLD [26].…”

Chemical Exposures Affect Innate Immune Response to SARS-CoV-2

“…Immunotoxic effects of many environmental and occupational chemical compounds have long been recognized [16]. Emerging evidence from experimental and population studies demonstrates the ability of a broad range of xenobiotics to interact with immunological pathways [17][18][19][20]. Thus, we hypothesize that specific immune response mechanisms may be synergistically affected by chemical exposures and SARS-CoV-2, resulting in increased severity of the disease.…”

“…In December 2019, a novel infectious disease was recognized [1]. The disease was named coronavirus disease 2019 (COVID- 19) and it is known now to be caused by coronavirus SARS-CoV-2. As of 20 March 2021, the COVID-19 pandemic has recorded almost 122 million cases with 2,694,094 mortalities spanning 223 countries of the world [2].…”

Environmental exposure to organophosphate esters and suspected non-alcoholic fatty liver disease among US adults: A mixture analysis

“…A number of risk factors, including exposure to environmental toxicants, play a role in the development and progression of NAFLD. Environmental factors may contribute to the development and progression of NAFLD through a variety of biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptor dysregulation, and disruption of inflammatory and immune-mediated signaling pathways (4)(5)(6). Furthermore, environmental contaminants might alter immune system components and hence influence immunological responses and disease susceptibility (4).…”