Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells
Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells
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DOI：
10.1152/ajpgi.00205.2016
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发表时间：
2017-03-01
影响因子：
4.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
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作者：
Brocker, Chad N.;Yue, Jiang;Gonzalez, Frank J.
过氧化物酶体增殖物激活受体-α（PPARA）是一种核转录因子，是全身脂质代谢的关键介质。啮齿类动物中的长期激活导致肝细胞增殖和肝细胞癌。关于非实质细胞（NPC）对PPARA介导的细胞增殖的贡献知之甚少。在肝细胞（Ppara（Delta Hep））和巨噬细胞（Ppara（Delta Mac））特异性Ppara缺失小鼠中评估NPC对PPARA激动剂诱导的肝肿大的贡献。用激动剂Wy-14643处理小鼠14天，并将条件无效小鼠的反应与常规敲除小鼠（Ppara（-/-））进行比较。Wy-14643治疗导致野生型和Ppara（Delta Mac）小鼠体重减轻和严重肝肿大，组织学分析显示特征性肝细胞肿胀; Ppara（Delta Hep）和Ppara（-/-）小鼠免受这些影响。Ppara（Delta Mac）血清化学以及天冬氨酸转氨酶和丙氨酸转氨酶水平与野生型小鼠匹配。与Ppara（-/-）小鼠相比，激动剂处理的Ppara（Delta Hep）小鼠血清胆固醇、磷脂和甘油三酯升高，表明肝外PPARA在调节循环脂质水平中可能起作用。BrdU标记证实仅在野生型和Ppara（Delta Mac）小鼠中细胞增殖增加。巨噬细胞PPARA破坏并不影响激动剂诱导的脂质代谢，细胞增殖，或DNA损伤和修复相关的基因表达上调，而基因表达在Ppara（德尔塔Hep）小鼠被抑制。有趣的是，炎性细胞因子IL-15和IL-18的下调依赖于巨噬细胞PPARA。在原代肝细胞和枯否细胞中证实了靶基因的细胞类型特异性调节。这些研究结论性地表明，细胞增殖仅由肝细胞中的PPARA活化介导，并且枯否细胞PPARA在介导PPARA激动剂的抗炎作用中具有重要作用。
Peroxisome proliferator-activated receptor-alpha (PPARA) is a nuclear transcription factor and key mediator of systemic lipid metabolism. Prolonged activation in rodents causes hepatocyte proliferation and hepatocellular carcinoma. Little is known about the contribution of nonparenchymal cells (NPCs) to PPARA-mediated cell proliferation. NPC contribution to PPARA agonist-induced hepatomegaly was assessed in hepatocyte (Ppara(Delta Hep))- and macrophage (Ppara(Delta Mac))- specific Ppara null mice. Mice were treated with the agonist Wy-14643 for 14 days, and response of conditional null mice was compared with conventional knockout mice (Ppara(-/-)). Wy-14643 treatment caused weight loss and severe hepatomegaly in wild-type and Ppara(Delta Mac) mice, and histological analysis revealed characteristic hepatocyte swelling; Ppara(Delta Hep) and Ppara(-/-) mice were protected from these effects. Ppara(Delta Mac) serum chemistries, as well as aspartate aminotransferase and alanine aminotransferase levels, matched wild-type mice. Agonist-treated Ppara(Delta Hep) mice had elevated serum cholesterol, phospholipids, and triglycerides when compared with Ppara(-/-) mice, indicating a possible role for extrahepatic PPARA in regulating circulating lipid levels. BrdU labeling confirmed increased cell proliferation only in wild-type and Ppara(Delta Mac) mice. Macrophage PPARA disruption did not impact agonist-induced upregulation of lipid metabolism, cell proliferation, or DNA damage and repair-related gene expression, whereas gene expression was repressed in Ppara(Delta Hep) mice. Interestingly, downregulation of inflammatory cytokines IL-15 and IL-18 was dependent on macrophage PPARA. Cell type-specific regulation of target genes was confirmed in primary hepatocytes and Kupffer cells. These studies conclusively show that cell proliferation is mediated exclusively by PPARA activation in hepatocytes and that Kupffer cell PPARA has an important role in mediating the anti-inflammatory effects of PPARA agonists.