Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis
Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis
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DOI：
10.1136/gut.2010.209551
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发表时间：
2011-09-01
期刊：
影响因子：
24.5
通讯作者：
Schwabe, Robert F.
中科院分区：
文献类型：
--
作者：
Kluwe, Johannes;Wongsiriroj, Nuttaporn;Schwabe, Robert F.
目的肝星状细胞（hepatic stellate cells，HSCs）的脂滴中含有包括类维生素A在内的多种生物活性代谢产物或其前体。脂滴和类维生素A的损失是HSC活化的标志，但尚不清楚这种损失是否促进HSC活化，肝纤维化或致癌。设计自发性和实验性纤维化以及二乙基亚硝胺诱导的肝癌在卵磷脂-视黄醇酰基转移酶（LRAT）缺陷的小鼠缺乏含维甲酸的脂滴在他们的HSCs.Results HSC激活后，LRAT表达迅速丢失，强调其在脂滴生物学在HSC的重要性。令人惊讶的是，在野生型和LRAT缺陷小鼠之间，胆管结扎（BDL）或四氯化碳（CCl（4））八次注射诱导的纤维化没有差异。为了排除由于HSC活化后LRAT的快速下调而错过对纤维形成的影响的可能性，研究了急性和自发性肝纤维化。然而，与野生型小鼠相比，3、8和12个月大的LRAT缺陷小鼠以及单次注射CCl后LRAT缺陷小鼠的纤维化没有增加（4）。为了确定HSC中缺乏类维生素A是否影响肝癌发生，野生型和LRAT缺陷小鼠注射二乙基亚硝胺。LRAT缺陷减少二乙基亚硝胺诱导的损伤和肿瘤负荷，并增加视黄酸响应基因Cyp 26 a1，RARb和p21的表达，这表明LRAT缺陷小鼠的肿瘤负荷较低是由于增加类维生素A信号传导和随后的p21介导的抑制增殖。结论缺乏含类维生素A的HSC脂滴不促进HSC活化，但减少肝癌发生。
Objective Hepatic stellate cells (HSCs) contain a number of bioactive metabolites or their precursors including retinoids in their characteristic lipid droplets. The loss of lipid droplets and retinoids is a hallmark of HSC activation, but it remains unclear whether this loss promotes HSC activation, liver fibrogenesis or carcinogenesis. Design Spontaneous and experimental fibrogenesis as well as a diethylnitrosamine-induced hepatocarcinogenesis were investigated in lecithin-retinol acyltransferase (LRAT)-deficient mice which lack retinoid-containing lipids droplets in their HSCs.Results Following HSC activation, LRAT expression was rapidly lost, emphasising its importance in lipid droplet biology in HSCs. Surprisingly, there was no difference in fibrosis induced by bile duct ligation (BDL) or by eight injections of carbon tetrachloride (CCl(4)) between wildtype and LRAT-deficient mice. To exclude the possibility that the effects on fibrogenesis were missed due to the rapid downregulation of LRAT following HSC activation, acute as well as spontaneous liver fibrosis was investigated. However, there was no increased fibrosis in 3-, 8- and 12-month-old LRAT-deficient mice and in LRAT-deficient mice after a single injection of CCl(4) compared with wild-type mice. To determine whether the absence of retinoids in HSCs affects hepatocarcinogenesis, wild-type and LRAT-deficient mice were injected with diethylnitrosamine. LRAT deficiency decreased diethylnitrosamine-induced injury and tumour load and increased the expression of the retinoic acid responsive genes Cyp26a1, RARb and p21, suggesting that the lower tumour load of LRAT-deficient mice was a result of increased retinoid signalling and subsequent p21-mediated inhibition of proliferation.Conclusions The absence of retinoid-containing HSC lipid droplets does not promote HSC activation but reduces hepatocarcinogenesis.