LncRNA PU.1 AS regulates arsenic-induced lipid metabolism through EZH2/Sirt6/SREBP-1c pathway
Graphical abstract
Introduction
Arsenic (As) is a metalloid element with various chemical forms, which is widely distributed in the environment and causing chronic or acute human health problems (Alamolhodaei et al., 2015, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2004, Rodriguezlado et al., 2013). Therefore, As was defined as one of human carcinogens by the International Cancer Research Center (ICRC). Over and above the carcinogenic effect, As exposure has been verified to induce multiple toxic effects and complications, including neurovirulence, dermal toxicity and nephrotoxicity (Abdul et al., 2015). Several researches have indicated that As exposure may influence lipid metabolism (Ameer et al., 2015, Paul et al., 2011). Such as the chronic exposure of low-dose As could alter lipogenic genes expression, and further disturb serum triglycerides (TG) levels (Adebayo et al., 2015). The lipid metabolism disorders caused by As exposure would contribute to the occurrence of cardiovascular diseases (Song et al., 2017). It is known that some renowned regulatory molecules play multiunit roles in the As-associated adverse biological effects, such as the sterol regulatory element binding proteins (SREBP) (Adebayo et al., 2015, Cheng et al., 2016). However, the underlying molecular mechanisms are not fully understood, whether there are other more molecules involved in the regulation still need intensive study.
Long non-coding RNAs (lncRNAs) are non-protein coding RNAs longer than 200 nucleotides (Dempsey and Cui, 2017). It is well documented that lncRNAs play multiform roles in the regulation of fundamental biological processes, such as the cell proliferation, cell differentiation, cell metabolism, carcinogenesis and so on (Batista and Chang, 2013, Schmitz et al., 2016). Recent years, more and more evidences have showed that lncRNAs are also widely involved in the regulation of lipid metabolism. For example, lncRNA HULC could increase cholesterol and TG levels through activating the master regulator of adipogenesis in hepatocellular carcinoma (Cui et al., 2015). The antisense lncRNA AdipoQ AS was identified to restrain adipogenesis by inhibiting the translation of adiponectin (Cai et al., 2018). In addition, lncRNAs are also participated in the environmental pollutions-induced toxicological responses and various human disorders (Geisler and Coller, 2013, Karlsson and Baccarelli, 2016). For instance, lncRNA LINC00341 played a key role in the PM2.5-induced G2/M phase cell cycle arrest (Xu et al., 2017). And lncRNA MALAT1 was authenticated to work in the As-induced liver carcinogenesis and malignant transformation through reciprocal regulation with HIF-2α (Luo et al., 2016). Our previous data uncovered that lncRNA UCA1 antagonized As-induced autophagy-dependent cell death (Gao et al., 2018). Nevertheless, whether lncRNAs also engage in As-induced lipid metabolism dysregulation are still unknown.
LncRNA PU.1 AS is the antisense of transcription factor PU.1, which is one member of the ETS (E-twenty six) family and plays a pivotal role in hematopoiesis via regulating numerous genes within the lymphocytes and myeloid progenitor populations (Carotta et al., 2010, Ebralidze et al., 2008). Recently, PU.1 AS was reported to facilitate adipogenesis through inhibiting the translation of PU.1 in preadipocytes (Pang et al., 2013, Wei et al., 2014). But in this article, our results showed that PU.1 AS levels were significantly increased in the liver of chronic As-feed mice which exhibiting decreased serum TG contents, further mechanism analyses revealed that PU.1 AS contributed to the lipid homeostasis through inhibiting the suppression role of its partner Enhancer of Zeste Homolog 2 (EZH2) in sirtuin 6 (Sirt6) mRNA and protein expression, which subsequently leading to the decreased expression of SREBP-1c and lipid accumulation. The present study would open a new insight to understand the regulation of lncRNAs in systemic lipid homeostasis when under As threaten.
Section snippets
Animal experiments
Six-week-old C57BL/6 male mice were obtained from Beijing Vital River Laboratory Animal Technology (Beijing, China). Mice were randomly grouped into the control group and As-treated group, and exposed to 0 or 50 mg/L sodium arsenite in drinking water for 5 weeks, a period in full compliance with chronic exposure. Water was freshly replenished every 3–4 days to minimize the oxidation of sodium arsenite. At the end of the exposure period, control and As-treated mice were sacrificed after
Chronic exposure to low-dose As reduces serum TG levels in mice
Detection of serum samples showed the TG concentrations were decreased significantly in As-treated mice compared with control group (p < 0.05) (Fig. 1a). As exposure had no significant effect on the levels of T-CHO, LDL-C and HDL-C (Fig. 1b, c, d). The weight measurements of body, liver and fat around epididymides did not show significant effects of As treatment (Fig. S1). As exposure did not cause significant liver toxicity, as no changes were observed in the CRP levels, AST levels and ALT
Discussion and conclusion
As is an omnipresent environmental toxicant and poses enormous threatens to human health (Jomova et al., 2011, Vahter, 2008). Till now, extensive studies have demonstrated that lipid metabolic disorders are the adverse biological effects in response to long-term As exposure (Afolabi et al., 2015, Kozulhorvath et al., 2012). Whereas, the potential molecular mechanisms of As-induced imbalance within lipid metabolism remain elusive. In the As exposure experiment, we observed that the serum TG
Acknowledgments
This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB14000000), the National Natural Science Foundation of China (Nos. 21507154, 21425731, 21637004 and 81570542). We thank the laboratory members for reagents and assistance with experiments.
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