Chu R, Madison L D, Lin Y, Kopp P, Rao M S, Jameson J L, Reddy J K
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11593-7. doi: 10.1073/pnas.92.25.11593.
Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase. Transfection assays in hepatoma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediated by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting amounts of retinoid X receptor (RXR) required for PPAR activation. Increasing amounts of RXR partially reversed the inhibition in a reciprocal manner; PPAR also inhibited TR activation. Results with heterodimerization-deficient TR and PPAR mutants further confirmed that interaction between PPAR and TR signaling systems is indirect. These results suggest that a convergence of the peroxisome proliferator and T3 signaling pathways occurs through their common interaction with the heterodimeric partner RXR.
过氧化物酶体增殖剂通过激活过氧化物酶体增殖物激活受体（PPAR）亚型，导致编码过氧化物酶体β-氧化系统酶的基因快速且协调的转录激活。由于甲状腺激素（T3；3,3',5-三碘甲状腺原氨酸）受体（TR）是核激素受体超家族的另一个成员，它调节与PPAR共享的一部分脂肪酸代谢基因，因此我们研究了过氧化物酶体增殖剂和T3信号通路之间相互作用的可能性。在携带与荧光素酶编码区融合的大鼠过氧化物酶体烯酰辅酶A水合酶/3-羟酰基辅酶A脱氢酶基因3.2 kb 5'-侧翼区的转基因小鼠中，T3抑制了环丙贝特诱导的荧光素酶活性以及内源性过氧化物酶体β-氧化酶。在肝癌H4-II-E-C3和CV-1细胞中的转染实验表明，这种抑制是由TR以配体依赖的方式介导的。凝胶迁移实验表明，TR对PPAR作用的调节是通过滴定PPAR激活所需的有限量视黄酸X受体（RXR）来实现的。增加RXR的量以相反的方式部分逆转了抑制作用；PPAR也抑制TR的激活。异源二聚化缺陷型TR和PPAR突变体的结果进一步证实，PPAR和TR信号系统之间的相互作用是间接的。这些结果表明，过氧化物酶体增殖剂和T3信号通路通过它们与异源二聚体伙伴RXR的共同相互作用而发生汇聚。
