Hepatic STAMP2 alleviates polychlorinated biphenyl‐induced steatosis and hepatic iron overload in NAFLD models

Abstract

Polychlorinated biphenyls (PCBs) have been associated with neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. Although the recent studies have demonstrated that PCB exposure leads to nonalcoholic fatty liver disease (NAFLD), the underlying mechanism has remained unsolved. In this study, we examined the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, and PCB 126 in C57BL/6 mice. Male C57Bl/6 mice were fed a standard diet or a 60% high-fat diet and exposed to Aroclor 1260 (10 mg/kg or 20 mg/kg) or PCB 126 (1 mg/kg or 5 mg/kg) by intraperitoneal injection for a total of four injections (2, 3, 4, and 5 weeks) for 6 weeks. In mice, both Aroclor 1260 and PCB 126-induced liver damage, hepatic steatosis and inflammation. We also observed that PCB exposure-induced hepatic iron overload (HIO). We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable therapeutic target for NAFLD patients. Thus, we further examined whether hepatic STAMP2 is involved in PCB-induced NAFLD. We observed that hepatic STAMP2 was significantly decreased in PCB-induced NAFLD models in vivo and in vitro. Furthermore, overexpression of hepatic STAMP2 using an adenoviral delivery system resulted in improvement of PCB-induced steatosis and HIO in vivo and in vitro. Our findings indicate that enhancing hepatic STAMP2 expression represents a potential therapeutic avenue for the treatment of PCB exposure-induced NAFLD.

Elevated SLC40A1 impairs cardiac function and exacerbates mitochondrial dysfunction, oxidative stress, and apoptosis in ischemic myocardia

“…However, to our knowledge, our study is the first to reveal an interaction between SLC40A1 and Steap4, which facilitated SLC40A1-mediated iron efflux. It has been documented that Steap4, unlike Steap3 which promotes iron uptake 38 , promotes intracellular iron excretion 39 , 40 . These results support our findings.…”

The Role of STAMP2 in Pathogenesis of Chronic Diseases Focusing on Nonalcoholic Fatty Liver Disease: A Review

“…Our previous study demonstrated that hepatic STAMP2 mediates recombinant FGF21-induced improvements in hepatic iron overload in nonalcoholic fatty liver disease through the upregulation of expression of the iron exporter, ferroportin [ 26 ]. In addition, we have also shown that hepatic STAMP2 alleviates polychlorinated biphenyl (PCB)-induced steatosis in NAFLD in in vivo and in vitro models [ 28 ]. These studies support that STAMP2 targeting could be a potential strategy for NAFLD accompanying HIO.…”

“…We previously showed that hepatic STAMP2 plays a pivotal role in alleviating either high-fat-diet (HFD)- or environmental-pollutant (polychlorinated biphenyl, PCB)-induced NAFLD and upregulation of STAMP2 using adenoviral STAMP2 ameliorates hepatic steatosis, inflammation, and iron overload in NAFLD, in in vivo and in vitro models [ 24 , 25 , 26 , 27 , 28 ]. Structurally, STAMP2 has metalloreductase activity and functions in iron and copper homeostasis [ 29 , 30 ].…”

Proinflammatory microglial response is a common mechanism of Aroclor 1254- and Tetrabromobisphenol-A-induced neurotoxicity in immature chronically exposed rats

“…Significant amounts of BFRs have spread throughout the world, even to West Africa [6] and the polar regions [29]. Several epidemiological reports have demonstrated the presence of these organic compounds in humans and wildlife [22,35,39] emphasizing their ability to accumulate in many tissues [16,19,38,42]. Both groups of compounds are character-ized by a high degree of lipophilicity, which allow them to preferentially accumulate in lipid-rich regions of the body such as adipose tissue and the brain.…”

“…It has been postulated that inflammatory processes may be involved in the toxicant-induced pathology in peripheral tissues. PCBs have been shown to activate a pro-inflammatory signalling cascade associated with atherosclerosis [4] and hepatic disorders [19], and participate in the development of inflammatory diseases [25]. 2,2',4,4',5,5'-heksachlorobiphenyl (PCB 153) has been shown to up-regulate the inflammatory enzyme cyclooxygenase-2 (COX-2) and the proinflammatory cytokines in human mast cells [20].…”