Bruschi Francesca Virginia, Claudel Thierry, Tardelli Matteo, Starlinger Patrick, Marra Fabio, Trauner Michael
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III Medical University of Vienna Vienna Austria.
Department of Surgery Medical University of Vienna Vienna Austria.
Hepatol Commun. 2019 Jul 15;3(9):1191-1204. doi: 10.1002/hep4.1395. eCollection 2019 Sep.
The patatin-like phospholipase domain-containing protein 3 () I148M variant predisposes to hepatic steatosis and progression to advanced liver injury with development of fibrosis, cirrhosis, and cancer. Hepatic stellate cells (HSCs) drive the wound healing response to chronic injury, and lack of liver X receptor (LXR) signaling exacerbates liver fibrogenesis by impairing HSC cholesterol homeostasis. However, the contribution of the I148M variant to this process is still unknown. We analyzed LXR expression and transcriptional activity in primary human HSCs and overexpressing LX-2 cells according to genotype (wild type [WT] versus I148M). Here we demonstrate that LXRα protein increased whereas LXR target gene expression decreased during activation of primary human HSCs. Notably, LXRα levels and signaling were reduced in primary I148M HSCs compared to WT, as displayed by decreased expression of LXR target genes. Moreover, reduced expression of cholesterol efflux and enzymes generating oxysterols was associated with higher total and free cholesterol accumulation whereas endogenous cholesterol synthesis and uptake were diminished in I148M HSCs. Luciferase assays on LXR response element confirmed decreased LXR transcriptional activity in I148M HSCs; in contrast the synthetic LXR agonist T0901317 replenished LXR functionality, supported by adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1) induction, and reduced collagen1α1 and chemokine (C-C motif) ligand 5 expression. Conversely, the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone had only partial effects on the LXR target gene ABCA1, and neither diminished expression of proinflammatory cytokines nor increased lipogenic genes in I148M HSCs. As a consequence of reduced PPARγ activity, HSCs carrying I148M show impaired LXR signaling, leading to cholesterol accumulation. The use of a specific LXR agonist shows beneficial effects for diminishing sustained HSC activation and development of liver fibrogenesis.
含帕他汀样磷脂酶结构域蛋白3（）I148M变体易导致肝脂肪变性，并随着纤维化、肝硬化和癌症的发展进展为晚期肝损伤。肝星状细胞（HSC）驱动对慢性损伤的伤口愈合反应，而肝X受体（LXR）信号的缺乏通过损害HSC胆固醇稳态加剧肝纤维化。然而，I148M变体对这一过程的贡献仍不清楚。我们根据基因型（野生型[WT]与I148M）分析了原代人HSC和过表达LX-2细胞中LXR的表达和转录活性。在此我们证明，在原代人HSC激活过程中，LXRα蛋白增加而LXR靶基因表达减少。值得注意的是，与WT相比，原代I148M HSC中LXRα水平和信号传导降低，LXR靶基因表达下降表明了这一点。此外，胆固醇流出和产生氧甾醇的酶的表达降低与总胆固醇和游离胆固醇积累增加相关，而I148M HSC中内源性胆固醇合成和摄取减少。对LXR反应元件的荧光素酶测定证实I148M HSC中LXR转录活性降低；相反，合成LXR激动剂T0901317补充了LXR功能，这由三磷酸腺苷结合盒亚家族A成员1（ABCA1）诱导支持，并降低了胶原1α1和趋化因子（C-C基序）配体5的表达。相反，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮对LXR靶基因ABCA1只有部分作用，既没有降低促炎细胞因子的表达，也没有增加I148M HSC中脂肪生成基因的表达。由于PPARγ活性降低，携带I148M的HSC显示LXR信号受损，导致胆固醇积累。使用特异性LXR激动剂对减少持续的HSC激活和肝纤维化发展显示出有益作用。
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