Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-γ, pioglitazone
Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-γ, pioglitazone
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DOI：
10.1124/jpet.102.047217
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Sato, N
中科院分区：
文献类型：
--
作者：
Enomoto, N;Takei, Y;Sato, N
过氧化物酶体增殖物激活受体 (PPAR)-γ 激动剂已被证明可以减少肿瘤坏死因子-α (TNF-α) 诱导的胰岛素抵抗。另一方面，库普弗细胞对脂多糖（LPS）的敏感性及其产生的TNF-α对于酒精性肝损伤的进展至关重要。本研究旨在确定吡格列酮（一种 PPAR-γ 激动剂）是否可以预防酒精引起的肝损伤。每24小时给大鼠灌胃一次乙醇(5g/kg体重)和吡格列酮(500μg/kg)。连续 8 周的乙醇导致肝脏出现明显的脂肪变性、坏死和炎症。吡格列酮大大降低了这些病理参数。乙醇处理 4 周后，Kupffer 细胞对 LPS 敏感，LPS (5 mg/kg) 诱导的肝脏病理恶化以及 LPS (100 ng/ml) 诱导的 Kupffer 细胞细胞内 Ca2+ 浓度升高增强。吡格列酮治疗使这些参数降低。 4 周乙醇组的 Kupffer 细胞 LPS 诱导的 TNF-α 产量比对照组高 3 至 4 倍。吡格列酮使这种增加减弱了 70%。 4周乙醇组的肠道通透性增加了10倍，吡格列酮治疗没有改变该值。在 Kupffer 细胞培养基中加入 TNF-α 可增强 CD14 表达、LPS 诱导的细胞内 Ca2+ 浓度反应以及 TNF-α 的产生。这些结果表明，吡格列酮通过消除库普弗细胞对 LPS 的敏感性来预防酒精性肝损伤。
Agonists of peroxisome proliferator-activated receptor (PPAR)-gamma have been shown to reduce tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF-alpha are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR-gamma agonist, could prevent alcohol-induced liver injury. Rats were given ethanol (5 g/kg b.wt.) and pioglitazone (500 mug/kg) once every 24 h intragastrically. Ethanol for 8 weeks caused pronounced steatosis, necrosis, and inflammation in the liver. These pathological parameters were diminished greatly by pioglitazone. Kupffer cells were sensitized to LPS after ethanol for 4 weeks as evidenced by aggravation of liver pathology induced by LPS (5 mg/kg) and enhancement of LPS (100 ng/ml)-induced intracellular Ca2+ concentration elevation in Kupffer cells. The parameters were diminished by treatment with pioglitazone. LPS-induced TNF-alpha production by Kupffer cells from the 4-week ethanol group was 3 to 4 times higher than control. This increase was blunted by 70% with pioglitazone. Gut permeability was 10-fold higher in the 4-week ethanol group, and pioglitazone treatment did not change the value. Inclusion of TNF-alpha in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca2+ concentration response, and production of TNF-alpha. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.