The effects of leptin, in concentrations seen in obesity, on collagen production and turnover in non-immortalized human hepatic stellate cell (HSC), were unknown. The profibrogenic effects of leptin in these cells were studied. Hepatic stellate cells were obtained from resected livers. Collagen I/III gene expression and protein production were measured by quantitative real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The signal transduction pathways involved were evaluated by specific blockers of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK), and Janus kinase 2 (JAK2). The effects on matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were assessed by their gene transcript levels, collagenolytic activity of cell culture supernatants, and MMP-1 protein levels. At concentrations seen in nonobese individuals ([leptin] < 10 ng/mL), leptin did not affect collagen production. At concentrations seen in obesity (30-50 ng/mL), leptin increased collagen I and III messenger RNA (mRNA) transcript levels by 286% +/- 55% (P < .001) and 167% +/- 62% (P < .007) and protein production by 45.8% +/- .02% and 84.39% +/- .01%, respectively. These effects were blocked by JAK2 inhibition as well as PI3K inhibition. Although MEK inhibition blocked leptin-induced procollagen I and III mRNA levels, there were no significant effects on collagen I and III protein levels. Leptin (10-50 ng/mL) had no significant effects on MMP-1 or TIMP-1 mRNA levels, collagenolytic activity, or MMP-1 protein levels. In conclusion, leptin, at levels seen in obese individuals, produces an increase in collagen production by HSC acting through the JAK and PI3K pathways. At these concentrations, leptin does not affect MMP-1 or TIMP-1 expression or collagenolytic activity of HSC.

译文

瘦素 (在肥胖中观察到的浓度) 对非永生化人肝星状细胞 (HSC) 中胶原蛋白产生和周转的影响尚不清楚。研究了瘦素在这些细胞中的促纤维化作用。从切除的肝脏中获得肝星状细胞。通过定量实时聚合酶链反应和十二烷基硫酸钠-聚丙烯酰胺凝胶电泳分别测量胶原蛋白I/III基因表达和蛋白质产生。通过磷脂酰肌醇3-激酶 (PI3K),丝裂原活化蛋白激酶激酶 (MEK) 和Janus激酶2 (JAK2) 的特异性阻滞剂评估了所涉及的信号转导途径。通过其基因转录水平,细胞培养上清液的胶原分解活性和MMP-1蛋白水平评估了对基质金属蛋白酶1 (MMP-1) 和组织金属蛋白酶1 (TIMP-1) 的影响。在非肥胖个体中观察到的浓度 ([leptin] < 10 ng/mL),leptin不会影响胶原蛋白的产生。在肥胖中观察到的浓度 (30-50 ng/mL),瘦素通过286% +/- 55% (P < .001) 和167% +/- 62% (P < .007) 增加胶原蛋白I和III信使RNA (mRNA) 转录水平,并通过45.8% +/- .02% 和84.39% +/- .01% 增加蛋白质生产。这些作用被JAK2抑制和PI3K抑制所阻断。尽管MEK抑制抑制了瘦素诱导的胶原蛋白I和III mRNA水平,但对胶原蛋白I和III蛋白水平没有显着影响。瘦素 (10-50ng/mL) 对MMP-1或TIMP-1 mRNA水平,胶原蛋白分解活性或MMP-1蛋白水平没有显着影响。总之,在肥胖个体中观察到的瘦素水平,通过HSC通过JAK和PI3K途径起作用而增加胶原蛋白的产生。在这些浓度下,瘦素不影响HSC的MMP-1或TIMP-1表达或胶原分解活性。

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