Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice.
Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice.
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DOI：
10.1210/en.2013-1592
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发表时间：
2013-12
期刊：
影响因子：
4.8
通讯作者：
Tomlinson JW
中科院分区：
文献类型：
--
作者：
Dowman JK;Hopkins LJ;Reynolds GM;Armstrong MJ;Nasiri M;Nikolaou N;van Houten EL;Visser JA;Morgan SA;Lavery GG;Oprescu A;Hübscher SG;Newsome PN;Tomlinson JW
非酒精性脂肪性肝病（NAFLD）与糖皮质激素过量和雄激素缺乏有关，但在大多数脂肪性肝炎患者中，循环皮质醇和雄激素水平正常。酶5α-还原酶（5αR）在雄激素和糖皮质激素作用中具有关键作用。我们推测5αR通过调节内分泌/旁分泌激素的利用率在脂肪性肝炎的发病机制中起重要作用。来自NAFLD患者和正常供体组织的人肝样品用于基因表达和免疫组织化学分析。使用Kleiner分类对NAFLD样品进行评分。此外，5只αR1−/−、5只αR2−/−和野生型（WT）小鼠喂食正常食物或美国生活方式诱导的肥胖综合征（ALIOS）饮食6或12个月。肝组织学分级和分期。肝脏和循环游离脂肪酸和甘油三酯水平进行了定量，基因和蛋白质表达进行了实时PCR和免疫组化测定。5αR1和5 α R2在人肝组织中高表达，且5αR1蛋白表达随NAFLD严重程度的增加而增加。喂食ALIOS饲料的5只αR1−/−（但不是5只αR2−/−）小鼠比WT小鼠发生了更严重的肝脏脂肪变性，并且参与胰岛素信号传导的基因的肝脏mRNA表达降低。此外，在ALIOS饮食12个月后，60%的WT小鼠发生了与肝细胞癌一致的局灶性肝细胞病变，而5αR2−/−小鼠为20%，5αR1−/−小鼠为0%（P < .05）。5αR1缺失可加速肝脂肪变性的发展，但可防止NAFLD相关肝细胞瘤形成，因此有可能成为治疗靶点。
Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.
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影响因子：
4.1
作者：
JAMDAR, SC
通讯作者：
JAMDAR, SC
DOI：
10.1073/pnas.87.10.3640
发表时间：
1990-05-01
影响因子：
11.1
作者：
ANDERSSON, S;RUSSELL, DW
通讯作者：
RUSSELL, DW
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
3.2
作者：
Konopelska, Sarah;Kienitz, Tina;Quinkler, Marcus
通讯作者：
Quinkler, Marcus
DOI：
10.1677/joe-10-0057
发表时间：
2010-08
期刊：
The Journal of endocrinology
影响因子：
--
作者：
Corcoran MP;Meydani M;Lichtenstein AH;Schaefer EJ;Dillard A;Lamon-Fava S
通讯作者：
Lamon-Fava S