Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
Toxicol Sci. 2011 Dec;124(2):299-310. doi: 10.1093/toxsci/kfr226. Epub 2011 Sep 2.
2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) induces hepatic dyslipidemia mediated by the aryl hydrocarbon receptor (AhR). Stearoyl-CoA desaturase 1 (Scd1) performs the rate-limiting step in monounsaturated fatty acid (MUFA) synthesis, desaturating 16:0 and 18:0 into 16:1n7 and 18:1n9, respectively. To further examine the role of Scd1 in TCDD-induced hepatotoxicity, comparative studies were performed in Scd1(+/+) and Scd1(-/-) mice treated with 30 μg/kg TCDD. TCDD induced Scd1 activity, protein, and messenger RNA (mRNA) levels approximately twofold. In Scd1(+/+) mice, hepatic effects were marked by increased vacuolization and inflammation and a 3.5-fold increase in serum alanine aminotransferase (ALT) levels. Hepatic triglycerides (TRGs) were induced 3.9-fold and lipid profiling by gas chromatography-mass spectroscopy measured a 1.9-fold increase in fatty acid (FA) levels, consistent with the induction of lipid transport genes. Induction of Scd1 altered FA composition by decreasing saturated fatty acid (SFA) molar ratios 8% and increasing MUFA molar ratios 9%. Furthermore, ChIP-chip analysis revealed AhR enrichment (up to 5.7-fold), and computational analysis identified 16 putative functional dioxin response elements (DREs) within Scd1 genomic loci. Band shift assays confirmed AhR binding with select DREs. In Scd1(-/-) mice, TCDD induced minimal hepatic vacuolization and inflammation, while serum ALT levels remained unchanged. Although Scd1 deficiency attenuated TCDD-induced TRG accumulation, overall FA levels remained unchanged compared with Scd1(+/+) mice. In Scd1(-/-) mice, TCDD induced SFA ratios 8%, reduced MUFA ratios 13%, and induced polyunsaturated fatty acid ratios 5% relative to treated Scd1(+/+) mice. Collectively, these results suggest that AhR regulation of Scd1 not only alters lipid composition but also contributes to the hepatotoxicity of TCDD.
2,3,7,8-四氯二苯并-对-二恶英（TCDD）通过芳香烃受体（AhR）诱导肝脂质代谢紊乱。硬脂酰辅酶 A 去饱和酶 1（Scd1）在单不饱和脂肪酸（MUFA）合成中发挥限速步骤的作用，将 16:0 和 18:0 分别去饱和为 16:1n7 和 18:1n9。为了进一步研究 Scd1 在 TCDD 诱导肝毒性中的作用，在 Scd1(+/+)和 Scd1(-/-)小鼠中进行了比较研究，这些小鼠用 30μg/kg TCDD 处理。TCDD 诱导 Scd1 活性、蛋白和信使 RNA（mRNA）水平增加约两倍。在 Scd1(+/+)小鼠中，肝效应表现为空泡形成和炎症增加，血清丙氨酸氨基转移酶（ALT）水平增加 3.5 倍。肝甘油三酯（TRG）增加 3.9 倍，气相色谱-质谱法测定的脂质谱显示脂肪酸（FA）水平增加 1.9 倍，这与脂质转运基因的诱导一致。Scd1 的诱导通过降低饱和脂肪酸（SFA）摩尔比 8%和增加 MUFA 摩尔比 9%来改变 FA 组成。此外，ChIP-chip 分析显示 AhR 富集（高达 5.7 倍），计算分析在 Scd1 基因组位点中鉴定出 16 个推定的功能性二恶英反应元件（DRE）。带移位分析证实 AhR 与选定的 DRE 结合。在 Scd1(-/-)小鼠中，TCDD 诱导的肝空泡形成和炎症最小，而血清 ALT 水平保持不变。尽管 Scd1 缺乏可减弱 TCDD 诱导的 TRG 积累，但与 Scd1(+/+)小鼠相比，总 FA 水平保持不变。在 Scd1(-/-)小鼠中，TCDD 诱导 SFA 比例增加 8%，MUFA 比例减少 13%，多不饱和脂肪酸比例增加 5%，与用 TCDD 处理的 Scd1(+/+)小鼠相比。总的来说，这些结果表明，AhR 对 Scd1 的调节不仅改变了脂质组成，而且还导致了 TCDD 的肝毒性。
