Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

Abstract

Perfluoroalkyl acids are widely used in numerous industrial and commercial applications due to their unique physical and chemical characteristics. Although perfluorooctanoic acid (PFOA) is associated with hepatomegaly through peroxisome proliferator-activated receptor α (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still be found in PPARα-null mice exposed to PFOA. To explore the potential effects of PFOA on sterol regulatory element-binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed a dose-dependent decrease and increase, respectively. Transcriptional activity of PPARα and SREBPs was significantly enhanced in livers. Protein expression analyzed by Western blotting showed that PFOA exposure stimulated SREBP maturation. Furthermore, proteins blocked SREBP precursor transport, insulin-induced gene 1 (INSIG1) and INSIG2 proteins, as well as a protein-mediated nuclear SREBP proteolysis, F-box and WD-40 domain protein 7, decreased in mouse liver exposed to PFOA. The expression levels of the miR-183-96-182 cluster, which is possibly involved in a regulatory loop intermediated by SREBPs maturation, were also increased in the mouse liver after PFOA exposure. We also observed that PFOA induced lipid content and PPARα in Hepa 1-6 cells after exposure to PFOA for 72 h but SREBPs were not activated in vitro. These results demonstrated that SREBPs were maturated by activating the miR-183-96-182 cluster-SREBP regulatory loop in PFOA-exposed mouse liver.

Perfluorooctanoic acid exposure alters polyunsaturated fatty acid composition, induces oxidative stress and activates the AKT/AMPK pathway in mouse epididymis

“…PFOA accumulation and its harmful effects on organ weight have also been reported in male mice livers and testes (Yan et al, 2014;Zhang et al, 2014a). When considering its toxic mechanisms, PFOA is often regarded as a fatty acid disrupting chemical, and exposure can cause lipid imbalance, including CHO, HDL, and TG disorders Yan et al, 2015). Lipid intracellular levels are balanced between TG synthesis and storage in lipid droplets (Ichimura et al, 2009;Miyauchi et al, 2010).…”

“…(SREBP) activation is crucial Yan et al, 2015). In relation to cellular lipid content, monoglyceride lipase (MGL) in most tissues regulates TG lipolysis (Dolinsky et al, 2004;Wendel et al, 2009), HMG-CoA reductase (HMG-COA R), APOA1 (Brundert et al, 2006), and NPC1 (Miller and Bose, 2011), which are responsible for CHO synthesis, uptake, and transfer, respectively.…”

Perfluorooctanoic acid exposure induces endoplasmic reticulum stress in the liver and its effects are ameliorated by 4-phenylbutyrate

“…218 RNA isolation and real-time PCR analysis were performed as described in our previous study 219 [22].…”

“…LDH activity from untreated cell lysates was also measured to 155 determine total LDH content. LDH activity in culture medium was measured to determine described in our previous study [22]. …”

“…Differences between only two treatment groups were determined via an 228 independent samples t-test. Differences between more than two treatment groups were 229 determined using one-way analysis of variance (ANOVA) followed by Fisher's least 237 Our previous studies suggested significant effects of PFOA on mouse liver after 238 exposure to PFOA for 28 d, including liver enlargement, serum ALT increase and activation 239 of hepatic SREBPs [3,22]. The content of PFOA was also increased in serum and livers of 240 mice after PFOA exposure [3,22].…”