PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells.
PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells.
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DOI：
10.1093/hmg/ddu121
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发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Romeo S
中科院分区：
文献类型：
--
作者：
Pirazzi C;Valenti L;Motta BM;Pingitore P;Hedfalk K;Mancina RM;Burza MA;Indiveri C;Ferro Y;Montalcini T;Maglio C;Dongiovanni P;Fargion S;Rametta R;Pujia A;Andersson L;Ghosal S;Levin M;Wiklund O;Iacovino M;Borén J;Romeo S
类维生素A是在视网膜和肝星状细胞（HSC）中以视黄酯形式储存的微量营养素。HSC是慢性肝病中纤维形成的关键参与者。负责从HSC中水解和释放视黄酯的酶尚不清楚，类维生素A代谢与肝脏疾病之间的关系仍不清楚。我们推测patatin-like phospholipase domain-containing 3（PNPLA 3）蛋白参与HSC中的视黄醇代谢。我们在原代人类HSC和患有非酒精性脂肪肝疾病的人类受试者队列（N = 146）中测试了我们的假设。在这里，我们表明PNPLA 3在人HSC中高度表达。其表达受视黄醇可用性和胰岛素调节，并且PNPLA 3表达增加导致脂滴含量减少。PNPLA 3促进响应于胰岛素的HSC的视黄醇的细胞外释放。我们还表明，纯化的野生型PNPLA 3将棕榈酸视黄酯水解成视黄醇和棕榈酸。相反，这种酶活性在纯化的PNPLA 3 148 M中显著降低，PNPLA 3 148 M是一种与肝纤维化和肝细胞癌发展密切相关的常见突变。我们还发现PNPLA 3 I148 M基因型是一个独立的（P = 0.009的多变量分析）循环视黄醇结合蛋白4，在人类中的视黄醇水平的可靠代理的决定因素。本研究将PNPLA 3鉴定为负责人类HSC中视黄基棕榈酸酯水解的脂肪酶。重要的是，这表明HSC，类维生素A代谢和PNPLA 3在确定慢性肝病易感性方面存在潜在的新联系。
Retinoids are micronutrients that are stored as retinyl esters in the retina and hepatic stellate cells (HSCs). HSCs are key players in fibrogenesis in chronic liver diseases. The enzyme responsible for hydrolysis and release of retinyl esters from HSCs is unknown and the relationship between retinoid metabolism and liver disease remains unclear. We hypothesize that the patatin-like phospholipase domain-containing 3 (PNPLA3) protein is involved in retinol metabolism in HSCs. We tested our hypothesis both in primary human HSCs and in a human cohort of subjects with non-alcoholic fatty liver disease (N = 146). Here we show that PNPLA3 is highly expressed in human HSCs. Its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression results in reduced lipid droplet content. PNPLA3 promotes extracellular release of retinol from HSCs in response to insulin. We also show that purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid. Conversely, this enzymatic activity is markedly reduced with purified PNPLA3 148M, a common mutation robustly associated with liver fibrosis and hepatocellular carcinoma development. We also find the PNPLA3 I148M genotype to be an independent (P = 0.009 in a multivariate analysis) determinant of circulating retinol-binding protein 4, a reliable proxy for retinol levels in humans. This study identifies PNPLA3 as a lipase responsible for retinyl-palmitate hydrolysis in HSCs in humans. Importantly, this indicates a potential novel link between HSCs, retinoid metabolism and PNPLA3 in determining the susceptibility to chronic liver disease.
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DOI：
10.1016/j.bbrc.2008.07.024
发表时间：
2008-09-26
影响因子：
3.1
作者：
Mello, Tommaso;Nakatsuka, Alice;Sanghani, Sonal P.
通讯作者：
Sanghani, Sonal P.
影响因子：
16.2
作者：
American Diabetes Association
通讯作者：
American Diabetes Association
影响因子：
4.9
作者：
Romeo, S.;Sentinelli, F.;Baroni, M. G.
通讯作者：
Baroni, M. G.
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
6.5
作者：
Lake, AC;Sun, Y;Gimeno, RE
通讯作者：
Gimeno, RE