Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis.
Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis.
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DOI：
10.1002/hep.28826
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发表时间：
2016-12
期刊：
影响因子：
13.5
通讯作者：
Boyer, James L.
中科院分区：
文献类型：
--
作者：
Kulkarni, Supriya R.;Soroka, Carol J.;Hagey, Lee R.;Boyer, James L.
Sirtuin1(Sirt1，酿酒酵母酶Sir2的哺乳动物同源物)是小鼠FXR的转录和反式激活调节因子，FXR是主要的胆汁酸(BA)感受器，在生理和病理生理条件下是BA代谢的关键调节因子。先前的研究表明，在胆汁淤积性肝损伤的啮齿动物模型中，Sirt1的表达受到了影响。我们假设Sirt1可能是减轻淤胆性肝损伤的潜在靶点。在原代培养的人肝细胞中，GCA处理后，SIRT1mRNA表达下调，可能是通过诱导miR-34a，而TUDCA诱导SIRT1表达，而不影响miR-34a表达。在3种小鼠肝损伤模型(胆管结扎、1%胆酸(CA)和MDR2−/−小鼠)中，SIRT1的表达也显著下调。饲喂CA饲料的小鼠也表现出肝脏FXR的高乙酰化和JNK/P53途径的诱导。饲喂CA饲料并同时给予Sirt1激活剂SRT1720(50 mg/kg/d)的小鼠，血浆ALT和BA水平分别下降了40%和45%。SRT1720通过增加三羟基化和四羟基化，减少二羟基BA组分来增加肝脏BA的亲水性。SRT1720还可能通过回肠Fgf15和FXR抑制Cyp7a1和Cyp27a1抑制肝脏BA的合成，同时增加肝脏BA的羟化与Cyp2b10的诱导有关。SRT1720可显著诱导肾组织中mRP2、mRP4、Pgc1α和CAR的表达，并使尿BA浓度增加约2倍。SRT1720通过增加小鼠肝组织BA成分的亲水性，增加尿中BA排泄，降低血浆BA浓度，从而减轻胆汁淤积性肝损伤。因此，使用Sirt1小分子激活剂为胆汁淤积性肝损伤提供了一个新的治疗靶点。
Sirtuin1 (Sirt1, mammalian homolog of S. Cerevisiae enzyme Sir2) is a transcriptional and transactivational regulator of murine Fxr, which is the primary bile acid (BA) sensor, and critical regulator of BA metabolism in physiological and pathophysiological conditions. Previous studies have suggested compromised Sirt1 expression in rodent models of cholestatic liver injury. We hypothesized that Sirt1 could be potentially targeted to alleviate cholestatic liver injury. In cultured primary human hepatocytes, SIRT1 mRNA was downregulated after GCA treatment, potentially via induction of miR-34a, whereas TUDCA induced SIRT1 expression without affecting miR-34a expression. Sirt1 expression was also significantly downregulated in three mouse models of liver injury (bile duct ligation, 1% cholic acid (CA) fed and the Mdr2−/− mouse). Mice fed CA diet also demonstrated hepatic FXR hyperacetylation and induction of the Jnk/p53 pathway. Mice fed CA diet and concurrently administered the Sirt1 activator; SRT1720 (50mg/kg/day, orally), demonstrated 40% and 45% decrease in plasma ALT and BA levels respectively. SRT1720 increased hepatic BA hydrophilicity by increasing tri- and tetra-hydroxylated and decreasing the di-hydroxylated BA fraction. SRT1720 administration also inhibited hepatic BA synthesis potentially via ileal Fgf15 and Fxr mediated inhibition of Cyp7a1 and Cyp27a1, along with increased hepatic BA hydroxylation in association with Cyp2b10 induction. SRT1720 administration significantly induced renal Mrp2, Mrp4, Pgc1α and Car expression along with ~2 fold increase in urinary BA concentrations. SRT1720 administration alleviates cholestatic liver injury in mice by increasing hydrophilicity of hepatic BA composition and decreasing plasma BA concentration via increased BA excretion into urine. Thus, use of small molecule activators of Sirt1 presents a novel therapeutic target for cholestatic liver injury.
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DOI：
10.1002/hep.27744
发表时间：
2015-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ghonem NS;Assis DN;Boyer JL
通讯作者：
Boyer JL
影响因子：
4.1
作者：
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通讯作者：
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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影响因子：
14.9
作者：
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DOI：
10.1016/j.bbapap.2009.11.023
发表时间：
2010-08
期刊：
Biochimica et biophysica acta
影响因子：
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作者：
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通讯作者：
Puigserver P