Fondevila Marcos F, Fernandez Uxia, Heras Violeta, Parracho Tamara, Gonzalez-Rellan Maria J, Novoa Eva, Porteiro Begoña, Alonso Cristina, Mayo Rebeca, da Silva Lima Natalia, Iglesias Cristina, Filliol Aveline A, Senra Ana, Delgado Teresa C, Woodhoo Ashwin, Herrero Laura, Serra Dolors, Prevot Vincent, Schwaninger Markus, López Miguel, Dieguez Carlos, Millet Oscar, Mato Jose M, Cubero Francisco J, Varela-Rey Marta, Iruzubieta Paula, Crespo Javier, Martinez-Chantar Maria L, Schwabe Robert F, Nogueiras Ruben
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
J Hepatol. 2022 Jul;77(1):15-28. doi: 10.1016/j.jhep.2022.02.003. Epub 2022 Feb 12.
BACKGROUND & AIMS: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored.
CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs.
Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor β1 (TGFβ1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFβ1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride.
These results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment.
We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs.
肝纤维化的发病机制需要肝星状细胞（HSCs）的激活；一旦被激活，肝星状细胞会失去细胞内脂肪酸，但脂肪酸氧化和肉碱棕榈酰转移酶1A（CPT1A）在此过程中的作用在很大程度上仍未得到探索。
在纤维化患者的肝星状细胞中发现了CPT1A。在人肝星状细胞系和原代肝星状细胞中对CPT1A进行了药理学和基因操作。最后，我们在肝星状细胞中特异性缺乏CPT1A的小鼠中诱导纤维化。
在此，我们表明非酒精性脂肪性肝炎患者的肝星状细胞中CPT1A表达升高，与纤维化评分呈正相关。在纤维化的啮齿动物以及原代人肝星状细胞和由转化生长因子β1（TGFβ1）和胎牛血清（FBS）激活的LX - 2细胞中也得到了证实。此外，CPT1A的药理学和基因沉默均通过降低线粒体活性来阻止TGFβ1和FBS诱导的肝星状细胞激活。饱和脂肪酸和活性氧诱导的CPT1A过表达会触发线粒体活性和纤维化标志物的表达。最后，肝星状细胞中特异性缺乏CPT1A的小鼠对胆碱缺乏的高脂肪饮食、蛋氨酸和胆碱缺乏的饮食或四氯化碳处理诱导的纤维化具有保护作用。
这些结果表明CPT1A在肝星状细胞的激活中起关键作用，并与肝纤维化的发展有关，使其成为纤维化治疗的潜在可操作靶点。
我们表明，在纤维化患者和纤维化小鼠模型的肝星状细胞中，肉碱棕榈酰转移酶1A（CPT1A）酶升高，并且CPT1A诱导这些细胞的激活。抑制CPT1A可通过阻止肝星状细胞的激活来改善纤维化。
