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.

Keywords: cytokines; flame retardants; interferon; metabolic disruption; metabolism-disrupting chemicals; nonalcoholic fatty liver disease.

Figure 1

Progression of NAFLD. Simple steatosis is the initial phase of NAFLD characterized by excessive accumulation of fat in the hepatocyte. With time, steatosis progresses to a more inflammatory state called NASH in approximately 59% of patients. In addition, 41% of patients can develop more severe conditions such as fibrosis and cirrhosis (40%), leading to hepatocellular carcinoma in 2–10% [1]. Steatosis, NASH, and fibrosis are reversible with timely and appropriate interventions, while later stages cannot be reversed. (Created with BioRender.com).

Figure 2

Structure similarity between thyroid hormone [thyroxine (T4) and triiodothyronine (T3)] and flame retardants (PBDE, e.g., 2,2′,4,4′,5-Pentabromodiphenyl ether (BDE-99), 2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47), 2,2′,4,4′,5,5′-Hexabromodiphenyl ether (BDE-153), and novel brominated flame retardant, e.g., Tetrabromobisphenol A).

Figure 3

Scheme showing role of FRs-mediated cytokine and IFNs production and potential contribution in the progression of NAFLD. DAMPS are produced by damaged cells and bind to PRRs such as TLRs and NLRs, or cytosolic DNA sensors (cGAS), resulting in downstream signaling leading to activation of inflammatory mediators, cytokines, and IFNs. IFNs function through the respective IFN receptors and downstream JAK–STAT signaling, leading to the expression of interferon stimulatory genes (ISGs), which modulate many biological processes involved in the progression of NAFLD. (Created with BioRender.com).

Figure 4

Schematic of FRs-mediated proposed mechanisms and pathways involved in the pathophysiology and progression of NAFLD. FRs, through several distinct mechanisms, could cause biochemical disruptions of many metabolic processes. FRs can induce direct mitochondrial damage or impair the mitochondria function and β-oxidation, thereby inducing ROS and inflammatory signaling. Alternatively, FRs could activate the NXRs. Since NRs are the central regulators of hepatic lipid metabolism, activation of NXR such as PXR could increase lipogenic gene expression, leading to increase de novo lipogenesis, inhibition of fatty acid β-oxidation, and increases in fatty acid import through upregulation of CD36. The impairment of mitochondrial β-oxidation induces the long-chain fatty acids metabolism via peroxisomal β-oxidation and ω-oxidation in the cytochromes. These processes further generate a considerably high amount of ROS, promoting oxidative stress, in turn inducing damage to the mitochondrial membranes, compromising cellular respiration and metabolism, and impairing liver function by cellular damage. Damaged mitochondria release the mtDNA into the cytosol, where it gets recognized as DAMPs by several PRR such as TLR or cGAS. cGAS is an innate immune sensor, which generates a second messenger cGMP and activates STING by translocating it to the perinuclear Golgi complex and serves as a signal for TBK1 and IKK. This promotes the phosphorylation and nuclear translocation of IRF3 and NF-κB inhibitor IκBα, and stimulation of IFN, whereas NF-κB translocation to the nucleus activates pro-inflammatory cytokines. In comparison, TLR activates either MyD88-dependent or TRIF-dependent signaling pathways and induces the expression of various inflammatory cytokines (TNFα, IL-1β, IL-6, IFNs). Cytokines, e.g., IFNs, bind to their respective receptors and initiate the downstream signaling, which phosphorylates and activates the transcription factors and initiates transcription of several IFN-related genes responsible for insulin resistance and activation of inflammatory mediators and de novo lipogenesis. Insulin resistance stimulates hyperinsulinemia, which increases glycolysis and promotes de novo lipogenesis by enhancing ChREBP and SREBP-1c, significantly contributing to lipid accumulation. Insulin resistance increases lipolysis, leading to increased free fatty acids delivery from the peripheral organs into the liver mediated by elevated CD36. Inflammatory mediators, such as IFNs, TNFα, and IL-6, may further decrease VLDL export and facilitate lipid accumulation. The net result is an escalation of hepatic steatosis and inflammatory condition, eventually leading to more severe NAFLD/NASH conditions. (Created using BioRender.Com).