Fatty Acid Desaturase 1 Influences Hepatic Lipid Homeostasis by Modulating the PPARα-FGF21 Axis.
Fatty Acid Desaturase 1 Influences Hepatic Lipid Homeostasis by Modulating the PPARα-FGF21 Axis.
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脂肪酸去饱和酶1通过调节PPARα-FGF 21轴影响肝脏脂质稳态
DOI：
10.1002/hep4.1629
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发表时间：
2021-03
影响因子：
5.1
通讯作者：
Liu W
中科院分区：
文献类型：
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作者：
Athinarayanan S;Fan YY;Wang X;Callaway E;Cai D;Chalasani N;Chapkin RS;Liu W
脂肪酸去饱和酶1 (FADS1)，也被称为δ - 5去饱和酶（D5D），是参与多不饱和脂肪酸（PUFAs）的去饱和和延伸级联反应生成长链PUFAs （LC - PUFAs）的限速酶之一。D5D功能降低、肝脏FADS1表达降低以及LC‐PUFAs水平低与非酒精性脂肪肝相关。然而，D5D在肝脂质稳态中的因果作用尚不清楚。在这项研究中，我们假设FADS1的下调会增加对肝脏脂质积累的易感性。我们使用体外和体内模型来验证这一假设，并描绘介导FADS1功能降低的分子机制。我们的研究表明，FADS1敲除显著降低了HepG2细胞中LC - PUFAs的细胞水平，增加了脂质积累和脂滴的形成。脂质积累与涉及脂质稳态的多种途径的显著改变有关，尤其是脂肪酸氧化。这些作用被证明是由过氧化物酶体增殖体激活受体α (PPARα) -成纤维细胞生长因子21 （FGF21）轴功能降低介导的，这可以通过二十二碳六烯酸、PPARα激动剂或FGF21治疗逆转。在体内，与野生型小鼠相比，饲喂高脂肪饲料的FADS1基因敲除小鼠肝脏脂肪变性增加。小鼠肝组织的分子分析在很大程度上证实了体外观察结果，特别是PPARα和FGF21蛋白表达降低。结论：综上所述，这些结果表明FADS1的失调通过下调PPARα - FGF21信号轴来改变肝脏脂质稳态。
The fatty acid desaturase 1 (FADS1), also known as delta‐5 desaturase (D5D), is one of the rate‐limiting enzymes involved in the desaturation and elongation cascade of polyunsaturated fatty acids (PUFAs) to generate long‐chain PUFAs (LC‐PUFAs). Reduced function of D5D and decreased hepatic FADS1 expression, as well as low levels of LC‐PUFAs, were associated with nonalcoholic fatty liver disease. However, the causal role of D5D in hepatic lipid homeostasis remains unclear. In this study, we hypothesized that down‐regulation of FADS1 increases susceptibility to hepatic lipid accumulation. We used in vitro and in vivo models to test this hypothesis and to delineate the molecular mechanisms mediating the effect of reduced FADS1 function. Our study demonstrated that FADS1 knockdown significantly reduced cellular levels of LC‐PUFAs and increased lipid accumulation and lipid droplet formation in HepG2 cells. The lipid accumulation was associated with significant alterations in multiple pathways involved in lipid homeostasis, especially fatty acid oxidation. These effects were demonstrated to be mediated by the reduced function of the peroxisome proliferator–activated receptor alpha (PPARα)–fibroblast growth factor 21 (FGF21) axis, which can be reversed by treatment with docosahexaenoic acid, PPARα agonist, or FGF21. In vivo, FADS1‐knockout mice fed with high‐fat diet developed increased hepatic steatosis as compared with their wild‐type littermates. Molecular analyses of the mouse liver tissue largely corroborated the observations in vitro, especially along with reduced protein expression of PPARα and FGF21. Conclusion: Collectively, these results suggest that dysregulation in FADS1 alters liver lipid homeostasis in the liver by down‐regulating the PPARα‐FGF21 signaling axis.
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DOI：
10.1016/j.bbrc.2007.06.068
发表时间：
2007-08-24
影响因子：
3.1
作者：
Lundasen, Thomas;Hunt, Mary C.;Rudling, Mats
通讯作者：
Rudling, Mats
影响因子：
25.7
作者：
Allard, Johane P.;Aghdassi, Elaheh;Heathcote, Jenny E.
通讯作者：
Heathcote, Jenny E.
影响因子：
6.5
作者：
Fan, Yang-Yi;Monk, Jennifer M.;Chapkin, Robert S.
通讯作者：
Chapkin, Robert S.
影响因子：
4.2
作者：
Jump, DB;Botolin, D;Demeure, O
通讯作者：
Demeure, O
影响因子：
30.8
作者：
通讯作者：
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