Department of Pathology, School of Medicine, Saint Louis University, St. Louis, MO, USA.
Hepatology. 2013 Jun;57(6):2202-12. doi: 10.1002/hep.26318. Epub 2013 May 15.
Activation of hepatic stellate cells (HSCs) is crucial to the development of fibrosis in nonalcoholic fatty liver disease. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation induces a fibrogenic gene program. Here we show that liver fatty acid-binding protein (L-Fabp), an abundant cytosolic protein that modulates fatty acid (FA) metabolism in enterocytes and hepatocytes, also modulates HSC FA utilization and in turn regulates the fibrogenic program. L-Fabp expression decreased 10-fold following HSC activation, concomitant with depletion of LDs. Primary HSCs isolated from L-FABP(-/-) mice contain fewer LDs than wild-type (WT) HSCs, and exhibit up-regulated expression of genes involved in HSC activation. Adenoviral L-Fabp transduction inhibited activation of passaged WT HSCs and increased both the expression of prolipogenic genes and also augmented intracellular lipid accumulation, including triglyceride and FA, predominantly palmitate. Freshly isolated HSCs from L-FABP(-/-) mice correspondingly exhibited decreased palmitate in the free FA pool. To investigate whether L-FABP deletion promotes HSC activation in vivo, we fed L-FABP(-/-) and WT mice a high-fat diet supplemented with trans-fatty acids and fructose (TFF). TFF-fed L-FABP(-/-) mice exhibited reduced hepatic steatosis along with decreased LD abundance and size compared to WT mice. In addition, TFF-fed L-FABP(-/-) mice exhibited decreased hepatic fibrosis, with reduced expression of fibrogenic genes, compared to WT mice.
L-FABP deletion attenuates both diet-induced hepatic steatosis and fibrogenesis, despite the observation that L-Fabp paradoxically promotes FA and LD accumulation and inhibits HSC activation in vitro. These findings highlight the importance of cell-specific modulation of hepatic lipid metabolism in promoting fibrogenesis in nonalcoholic fatty liver disease. (Hepatology 2013).
非酒精性脂肪性肝病纤维化发展的关键是肝星状细胞（HSCs）的激活。静止的 HSCs 含有脂滴（LDs），其在激活时的耗竭会诱导纤维生成基因程序。在这里，我们表明，肝脏脂肪酸结合蛋白（L-Fabp）是一种丰富的细胞质蛋白，可调节肠细胞和肝细胞中的脂肪酸（FA）代谢，也可调节 HSC FA 的利用，并反过来调节纤维生成程序。HSC 激活后，L-Fabp 的表达减少了 10 倍，同时 LDs 也减少了。从 L-FABP（-/-）小鼠中分离的原代 HSCs 比野生型（WT）HSCs 含有更少的 LDs，并且表现出参与 HSC 激活的基因表达上调。腺病毒 L-Fabp 转导抑制传代 WT HSCs 的激活，并增加促增殖基因的表达，同时增加细胞内脂质积累，包括甘油三酯和 FA，主要是棕榈酸。从 L-FABP（-/-）小鼠中分离的新鲜 HSCs 相应地表现出游离 FA 池中的棕榈酸减少。为了研究 L-FABP 缺失是否促进体内 HSC 激活，我们用富含反式脂肪酸和果糖（TFF）的高脂肪饮食喂养 L-FABP（-/-）和 WT 小鼠。与 WT 小鼠相比，TFF 喂养的 L-FABP（-/-）小鼠表现出肝脂肪变性减少，同时 LD 丰度和大小减少。此外，与 WT 小鼠相比，TFF 喂养的 L-FABP（-/-）小鼠表现出肝纤维化减少，纤维化基因表达减少。
尽管观察到 L-Fabp 反常地促进 FA 和 LD 积累并抑制体外 HSC 激活，但 L-FABP 缺失可减轻饮食诱导的肝脂肪变性和纤维化。这些发现强调了在非酒精性脂肪性肝病中促进纤维化时，细胞特异性调节肝脂质代谢的重要性。（Hepatology 2013）。
