Coronary heart disease:Significance of liver X receptor α genomics

Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease(CHD).In this regard ligand activated liver X receptor(LXR)-α has emerged as a key molecular switch by its inherent ability to modulate an array of genes involved in these two fundamental cellular processes.In addition,LXR-α has also been found to play a role in hepatic lipogenesis and innate immunity.Although several lines of evidence in experimental model systems have established the atheroprotective nature of LXR-α,human subjects have been reported to possess a paradoxical situation in which increased blood cellular LXR-α gene expression is always accompanied by increased coronary occlusion.This apparent paradox was resolved recently by the finding that CHD patients possess a deregulated LXR-α transcriptome due to impaired ligand-receptor interaction.This blood cellular mutated LXR-α gene ex- pression correlated specifically with the extent of coro- nary occlusion and hence need is felt to devise new synthetic ligands that could restore the function of this mutated LXR-αprotein in order to modulate genes involved in reverse cholesterol transport and suppression of the inflammatory response leading to the effective treatment of CHD.

Pravastatin activates the expression of farnesoid X receptor and liver X receptor alpha in Hep3B cells

BACKGROUND: Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among the nuclear hormone receptors that regulate cholesterol-bile acid metabolism in the nuclei of hepatocytes. However, there is controversy over whether or how statins change the expression of peroxisome proliferator-activated receptor(PPAR)α, PPARγ, liver X receptor α(LXRα), farnesoid X receptor(FXR), ABCG5, ABCG8, and 7α-hydroxylase(CYP7A1) which are directly involved in the cholesterol saturation index in bile. METHODS: Human Hep3B cells were cultured on dishes. MTT assays were performed to determine the appropriate concentrations of reagents to be used. The protein expression of PPARα and PPARγ was measured by Western blotting analysis, and the mRNA expression of LXRα, FXR, ABCG5, ABCG8 and CYP7A1 was estimated by RT-PCR. RESULTS: In cultured Hep3B cells, pravastatin activated PPARα and PPARγ protein expression, induced stronger expression of PPARγ than that of PPARα, increased LXRα mRNA expression, activated ABCG5 and ABCG8 mRNA expression mediated by FXR as well as LXRα, enhanced FXR mRNA expression, and increased CYP7A1 mRNA expression mediated by the PPARγ and LXRα pathways, together or independently. CONCLUSION: Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRαand CYP7A1 in human hepatocytes.

Liver X receptors and epididymal epithelium physiology

瞄准：在鼠科的附睾头在类脂化合物作文和基因表示规定调查肝 X 受体(LXR ) 的角色。LXR 是为 oxysterols 的原子受体，分子源于作为二 isoforms 在哺乳动物是在场的胆固醇新陈代谢：LXR α，是明确地在类脂化合物使物质替换纸巾表示的更多，脂肪质并且 steroidogenic 纸巾，和巨噬细胞，而 LXR β是无所不在的。在繁殖生理学的 Theirimportance 被两 LXR 的功能在被破坏了的雄的老鼠有富饶骚乱在 5 个月岁时开始的事实支撑了，导致到 9 个月的年龄的完全的绝育。这些缺点在头片断与 epididymalepithelial 退化被联系一和二，并且与一个精子中间的片脆弱，当钠满足时，导致孤立的精子头和毛虫的存在从附睾尾被恢复。方法：野类型的 andLXR 缺乏的老鼠的附睾头的类脂化合物作文用油红Ｏ在织物 cryosections 上染色被估计，类脂化合物抽取由高效液相色谱法或煤气的层析列在后面。基因表示被量的实时聚合酶链反应检查。结果：用 LXR 缺乏的鼠标，我们显示出附睾头的类脂化合物作文以及编码 SREBPlc， SCD1 和 SCD2 的基因的一个显著地减少的表达式的改变，在脂肪酸新陈代谢包含了。结论：总的来说， LXR 是重要管理者 ofepididymal 的这些结果表演工作，并且在成熟处理发生在精子附睾成熟期间的类脂化合物起一个关键作用。

Role of liver X receptors alpha agonist on expressions of LPS-induced inflammatory response associated factor IRAK-4 and NF-kappaB in Kupffer cells

在 interleukin-1 受体的表情上探索激活的肝 X 受体(LXR ) 的角色的目的在在 Kupffer 房间并且到由 LPS 导致了的煽动性的反应联系了 kinase-4 (IRAK-4 ) 和 NF-kappaB (NF-B ) 调查煽动性的反应的 LXR 否定规定的可能的机制。Kupffer 房间被骨胶原灌注在 situ 从男 Kunming 老鼠孤立的方法。并且这些房间被划分成 4 个组：正常控制组， LPS 处理组， LXR 收缩筋 T0901317 处理组， LPS 和 T0901317 联合了处理组。 LPS 处理组在 RPMI 1640 与 1 g/ml LPS 的最后的集中被对待并且为 6 h 有教养， T0901317 处理组在 RPMI 1640 与 5 g/ml 的最后的集中被对待并且为 24 h 有教养，并且联合处理组在 RPMI 1640 与 1 g/ml T0901317 的最后的集中为 24 h 收到了文化前然后为有在 RPMI 1640 的 5 g/ml LPS 的最后的集中的 6 h 有教养。所有组为 30 h 是有教养的。在 mRNA 和蛋白质层次的 LXR， IRAK-4 和 NF-B 的表示被即时 PCR 并且西方的弄污检测，并且 TNF-1 和 IL-1 层次被 ELISA 检测。LXR mRNA 和蛋白质的层次是的结果在 LPS 组在 T0901317 组最高、最低(P < 0.05 ) 。IRAK4 和 NF-B mRNAs 和蛋白质的水平比在 LPS 组在联合对待的组是显然更低的(P < 0.05 ) 。并且 TNF-1 和 IL-1 的水平在 LPS 组最高被观察(P < 0.05 ) ，但是在控制组， T0901317 组和联合对待的组之中的没有差别(P > 0.05 ) 。这些标明日期的结论建议 LXR 收缩筋有效地装起来调整 LXR mRNA 和蛋白质的表情并且禁止煽动性的反应。这可能经由下面调整在 mRNA 和蛋白质层次的 IRAK4 和 NF-B 的表情。

Effect of Dangfei Liganning capsule(当飞利肝宁胶囊) on liver X receptor α/steroid regulatory element binding protein-1/fatty acid synthase signal pathway in rats with metabolic-associated fatty liver disease

OBJECTIVE: To study the mechanism of Dangfei Liganning capsule(当飞利肝宁胶囊) in the treatment of rats with metabolic associated fatty liver disease(MAFLD). METHODS: Totally 48 specific pathogen free SpragueDawley male rats were randomly divided into normal Group, model group, Dangfei Liganning high, moderate, and low-dose groups and Essentiale group which were fed with high fat diet for 8 weeks, and gavage and molding were carried out simultaneously. Dangfei Liganning high, middle and low-dose group were given 0.27, 0.135 and 0.0675 g·kg-1·d-1 respectively by gavage, Essentiale group was given 0.123 g·kg-1·d-1 by gavage, the same amount of distilled water was given by gavage in the normal group and the model group. The rats were weighed at the 0th week, 2nd week, 4th week, 6th week and 8th weekend respectively. The rats were sacrificed at the end of the 8th week. Serum levels of alanine aminotransferase(ALT), alanine aminotransferase(AST),triglyceride(TG), total cholesterol(CHO), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein (LDL-C), total protein(TP), albumin(Alb), globulin(GLB), total bilirubin(TBIL), direct bilirubin(DBIL), tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) were measured. The levels of liver tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and liver pathology [hematoxylin and eosin(HE) staining, oil red O staining] were detected. The expression levels of liver X receptor α(LXRα), steroid regulatory element binding protein-1(SREBP-1) and fatty acid synthase(FAS) were detected by immunohistochemistry, Western blot and reverse transcription-polymerase chain reaction reverse transcription-polymerase chain reaction. RESULTS: From the beginning to the 8th week, the growth rate of body weight in the Dangfei Liganning highdose group was slower than all other groups. There was no significant difference in ALB level in all groups(P > 0.05). Compared with the model group, the levels of ALT, AST, LDL-C, TG, CHO, TP, GLB, TBIL, DBIL, IL-6, TNF-α were significantly decreased and HDL-C were significantly increased in Dangfei Liganning high-dose group(P < 0.01, < 0.05). HE and oil red O staining showed that the fatty lesions in rat liver were alleviated, while the expressions of LXRα, SREBP-1, FAS m RNA and protein were significantly decreased(P < 0.01). CONCLUSIONS: Dangfei Liganning capsule can slow down the increase of body weight of MAFLD rats, reduce the levels of transaminase, Lipid and inflammatory factors in MAFLD rats, promote the synthesis of liver protein and bile metabolism, and improve the liver fatty lesion of MAFLD rats, among which the Dangfei Liganning highdose group is more effective. The mechanism of action may be through blocking LXR-SREBP-1-FAS signal pathway.

ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers

Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.

Natural modulators of liver X receptors

Nuclear receptor transcription factors are ligand-activated proteins that control various biological events from cell growth and development to lipid metabolism, and energy and glucose homeostasis. Nuclear receptors are important drug targets for metabolic diseases. Liver X receptors(LXRs) are nuclear receptor transcription factors that play essential roles in regulation of cholesterol, triglyceride, fatty acid, and glucose homeostasis. LXR-defi cient mice have shown the association of LXR-signaling pathway dysfunction with several human pathologies including atherosclerosis, hyperlipidemia, Alzheimer's disease and cancer. Thus, LXRs are promising pharmacological targets for these diseases. Synthetic LXR agonists may lower cholesterol, but increase triglyceride and induce fatty liver. The naturally occurring LXR ligands, with moderate activity, may serve as nutraceuticals for prevention or treatment of the disorders, while minimizing potential side effects. In this review, recent advances in natural LXR modulators are summarized including agonist, antagonist and the modulator of LXR pathway.

Liver X receptor agonist T0901317 reduces atherosclerotic lesions in apoE^(-/-) mice by up-regulating NPC1 expression

In this study, we studied the effect of liver X receptor (LXR) agonist T0901317 on Niemann-Pick C1 protein (NPC1) expression in apoE-/- mice. Male apoE-/- mice were randomized into 4 groups, baseline group (n=10), control group (n=14), treatment group (n=14) and prevention group (n=14). All of the mice were fed with a high-fat/high-cholesterol (HFHC) diet containing 15% fat and 0.25% cholesterol. The baseline group treated with vehicle was sacrificed after 8 weeks of the diet. The control group and the prevention group were treated with either vehicle or T0901317 daily by oral gavage for 14 weeks. The treatment group was treated with vehicle for 8 weeks, and then was treated with the agonist T0901317 for additional 6 weeks. Gene and protein expression was analyzed by real-time quantitative PCR, immunohistochemistry and Western blotting, respectively. Plasma lipid concentrations were measured by commercially enzymatic methods. We used RNA interference technology to silence NPC1 gene expression in THP-1 macrophage-derived foam cells and then detected the effect of LXR agonist T0901317 on cholesterol efflux. Plasma triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 treatment reduced the aortic atherosclerotic lesion area by 64.2% in the prevention group and 58.3% in the treatment group. LXR agonist treatment increased NPC1 mRNA expression and protein levels in the small intestine, liver and aorta of apoE-/- mice. Compared with the normal cells, cholesterol efflux of siRNA THP-1 macrophage-derived foam cells was significantly decreased, whereas cholesterol efflux of LXR agonist T0901317-treated THP-1 macrophage-derived foam cells was significantly increased. Our results suggest that LXR agonist T0901317 inhibits atherosclerosis development in apoE-/- mice, which is related to up-regulating NPC1 expression.

Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor(FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor(PXR) is a ligandactivated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gutliver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. Pub Med was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.

FXR激动剂在非酒精性脂肪性肝炎治疗中的研究进展

非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis,NASH),又称代谢性脂肪性肝炎,是病理变化与酒精性肝炎相似但无过量饮酒史的临床综合征,好发于中年特别是超重肥胖个体。非酒精性脂肪性肝炎与肥胖、胰岛素抵抗、2型糖尿病、高脂血症等代谢紊乱关系密切,主要特征为肝细胞大泡性脂肪变伴肝细胞损伤和炎症,严重者可发展为肝硬化,但至今NASH尚无得到批准的治疗方案。在寻找有效的治疗方法时,解决代谢失调、炎症和抗纤维化的新策略不断涌现。法尼类X受体(Farnesoid X receptor,FXR)除了是胆汁酸代谢和肠肝循环的关键调节剂外,还参与调节代谢稳态,使其成为NASH中有吸引力的治疗靶点。本文综述了FXR激动剂对NASH治疗的研究进展。

The LXRB-SREBP1 network regulates lipogenic homeostasis by controlling the synthesis of polyunsaturated fatty acids in goat mammary epithelial cells

Background:In rodents,research has revealed a role of liver X receptors(LXR) in controlling lipid homeostasis and regulating the synthesis of polyunsaturated fatty acids(PUFA).Recent data suggest that LXRB is the predominant LXR subtype in ruminant mammary cells,but its role in lipid metabolism is unknown.It was hypothesized that LXRB plays a role in lipid homeostasis via altering the synthesis of PUFA in the ruminant mammary gland.We used overexpression and knockdown of LXRB in goat primary mammary epithelial cells(GMEC) to evaluate abundance of lipogenic enzymes,fatty acid profiles,content of lipid stores and activity of the stearoyl-Co A desaturase(SCD1) promoter.Results:Overexpression of LXRB markedly upregulated the protein abundance of LXRB while incubation with si RNA targeting LXRB markedly decreased abundance of LXRB protein.Overexpression of LXRB plus T0901317(T09,a ligand for LXR) dramatically upregulated SCD1 and elongation of very long chain fatty acid-like fatty acid elongases 5–7(ELOVL 5–7),which are related to PUFA synthesis.Compared with the control,cells overexpressing LXRB and stimulated with T09 had greater concentrations of C16:0,16:1,18:1n7,18:1n9 and C18:2 as well as desaturation and elongation indices of C16:0.Furthermore,LXRB-overexpressing cells incubated with T09 had greater levels of triacylglycerol and cholesterol.Knockdown of LXRB in cells incubated with T09 led to downregulation of genes encoding elongases and desaturases.Knockdown of LXRB attenuated the increase in triacylglycerol and cholesterol that was induced by T09.In cells treated with dimethylsulfoxide,knockdown of LXRB increased the concentration of C16:0 at the expense of C18:0,while a significant decrease in C18:2 was observed in cells incubated with both si LXRB and T09.The abundance of sterol regulatory element binding transcription factor 1 precursor(p SREBP1) and its mature fragment(n SREBP1) was upregulated by T09,but not LXRB overexpression.In the cells cultured with T09,knockdown of LXRB downregulated the abundance for p SREBP1 and n SREBP1.Luciferase reporter assays revealed that the activities of wild type SCD1 promoter or fragment with SREBP1 response element(SRE) mutation were decreased markedly when LXRB was knocked down.Activity of the SCD1 promoter that was induced by T09 was blocked when the SRE mutation was introduced.Conclusion:The current study provides evidence of a physiological link between the LXRB and SREBP1 in the ruminant mammary cell.An important role was revealed for the LXRB-SREBP1 network in the synthesis of PUFA via the regulation of genes encoding elongases and desaturases.Thus,targeting this network might elicit broad effects on lipid homeostasis in ruminant mammary gland.

法尼醇X受体激动剂对非酒精性脂肪性肝炎治疗作用研究进展

代谢相关脂肪性肝病(metabolic dysfunction-associated fatty liver disease,MAFLD)的全球患病率为20%~40%,伴随着沉重的疾病负担和晚期疾病相关的高病死率,目前尚无批准治疗MAFLD的标准药物。法尼醇X受体(farnesoid X receptor,FXR)具有调控糖脂代谢和改善胰岛素抵抗的作用,其中奥贝胆酸作为FXR激动剂,已被多项研究证实可改善MAFLD患者的肝组织学特征。本文主要阐述FXR激动剂的作用机制和研究现状以供临床参考。

Reduction in Bile Acid Pool Causes Delayed Liver Regeneration Accompanied by Down-regulated Expression of FXR and C-Jun mRNA in Rats

The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile acid size,and then a partial hepatectomy(PH)was performed.Rats fed on the normal diet served as the controls.Measurements were made on the rate of liver regeneration,the labeling indices of PCNA,the plasma total bile acids(TBA),and the mRNA expression of cholesterol 7alpha-hydroxylase(CYP7A1),farnesoid X receptor(FXR),and transcription factor c-Jun or c-fos.As compared with the normal and CA groups,the rate of liver regeneration was decreased on the day 3,and 7 after PH;the peak of the labeling indices of PCNA was delayed and the labeling indices were significantly reduced on the day 1;the TBA were also decreased on the day 1;the expression of FXR decreased but that of CYP7A1 increased at any given time;at the 1st,and 3rd h,the expression of c-Jun was declined in the cholestyramine group.The reduction in the bile acid pool size was found to delay the liver regeneration,which may be caused by the down-regulation of FXR and c-Jun expression.

肝X受体激动剂对抑郁模型小鼠海马树突棘数目的影响

目的:探讨肝X受体(LXRs)激动剂GW3965对慢性不可预知性应激(CUS)诱导的抑郁症模型小鼠海马结构各亚区CA1、CA3和DG内树突棘数目变化的影响。方法:选取雄性C57BL/6J小鼠,经过适应性喂养和糖水基线调整后,被随机分为对照组(control)、对照+GW3965组(GW)、抑郁模型组(CUS)以及抑郁模型+GW3965组(CUS/GW)。CUS组和CUS/GW组小鼠接受连续10周的CUS干预,GW组和CUS/GW组小鼠在CUS干预的第7周开始接受4周的GW3965给药。第10周末进行行为学测试,之后应用免疫组化及现代体视学技术精准定量小鼠海马结构各亚区树突棘密度和总数目改变。结果:持续数周的应激使小鼠的体质量及糖水偏好百分比明显下降,强迫游泳不动时间显著增加。体视学结果显示CUS干预使小鼠CA1、CA3和DG区树突棘密度和数量明显减少。4周GW3965治疗改善了小鼠的抑郁样行为及逆转了DG区树突棘密度和总数目的下降。结论:LXRs激动剂GW3965对CUS模型小鼠DG区树突棘总数目的影响可能是其发挥抗抑郁作用的神经生物学基础之一。

沙棘熊果酸对酒精性肝损伤大鼠肝FXR信号通路的影响

目的:初步探讨沙棘熊果酸对酒精性肝损伤大鼠肝法尼醇X受体(Farnesoid X receptor,FXR)信号通路关键蛋白表达的影响。方法:6周龄SPF级SD大鼠随机分为4组,每组9只,分别为正常对照组、酒精模型组、熊果酸对照组和熊果酸+酒精组,干预时间为8周。采用苏木精-伊红(H&E)染色法观察大鼠肝组织病理学变化;测定大鼠血清中谷丙转氨酶(Alanine aminotransferase,ALT)、谷草转氨酶(Aspartateaminotransferase,AST)活力和血清总胆汁酸(Total bile acid,TBA)、肝脏甘油三酯(Triglyceride,TG)、总胆固醇(Total cholesterol,TC)含量;酶联免疫吸附(Enzyme linked immunosorbent assay,ELISA)法检测血清细胞因子肿瘤坏死因子α(Tumor necrosis factor-α,TNF-α)、白细胞介素1β(Interleukin 1β,IL-1β)、白细胞介素10(Interleukin 10,IL-10)含量;免疫印迹法(Western blotting)测定大鼠肝FXR信号通路相关蛋白表达情况。结果:与正常对照组相比,酒精模型组大鼠肝脏存在大小不一的脂肪空泡和大量炎性细胞浸润;血清ALT、AST活力,TNF-ɑ、IL-1β水平,TBA含量和肝脏TG、TC含量均显著升高(P<0.05)、IL-10水平显著下降(P<0.05)。经熊果酸干预后,肝脏脂肪变性得到明显改善,炎性细胞浸润减少;血清ALT、AST活力,TNF-α、IL-1β水平,TBA含量和肝脏TG含量均有不同程度的显著下降(P<0.05),IL-10水平显著提高(P<0.05)。Western blotting结果显示,与正常对照组相比,模型组大鼠肝脏FXR蛋白表达显著降低(P<0.05),CYP7A1和SREBP-1c蛋白表达均显著升高(P<0.05);而经熊果酸干预后,FXR蛋白表达明显提高,CYP7A1及SREBP-1c蛋白表达明显下调,且差异均具有统计学意义(P<0.05)。结论:沙棘熊果酸能够明显改善酒精诱导的肝脏损伤,其作用机制可能与上调肝FXR、抑制CYP7A1和SREBP-1c的蛋白表达,从而维胆汁酸稳态、调节脂质代谢有关。

Gut-liver axis signaling in portal hypertension

Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.

孕马血清促性腺激素对小鼠肝脏组织CYP17A1和PXR表达的影响

旨在了解孕马血清促性腺激素(pregnant mare serum gonadotropin,PMSG)对小鼠肝脏细胞色素P45017A1(cytochrome P45017A1,CYP17A1)和孕烷X受体(pregnane X receptor,PXR)表达的影响。将48只雌性昆明系小鼠随机分为PMSG处理组和对照组,PMSG组小鼠腹腔注射PMSG 10 IU,注射后12、24、48 h处死12只小鼠,采血分离血清并采集肝脏组织样本;对照组腹腔注射等体积生理盐水,在注射后12、24、48 h时采集4只小鼠的血液和肝脏组织样本。酶联免疫吸附试验(ELISA)检测血清PMSG含量,苏木精-伊红染色(HE)观察PMSG对肝脏组织的影响,RT-qPCR和Western blot检测肝脏组织CYP17A1和PXR表达水平,免疫组织化学染色检测CYP17A1和PXR在肝脏组织中的定位。结果显示,PMSG注射后12 h小鼠血清中PMSG含量显著升高(P<0.05),24 h和48 h时逐渐降低,但仍显著高于NC组(P<0.05);PMSG注射后12、24、48 h时,肝脏细胞水泡变性明显;注射PMSG后肝脏组织中CYP17A1和PXR基因和蛋白表达均显著下调(P<0.05);CYP17A1和PXR主要定位于肝索肝实质细胞质中。研究结果证明,PMSG能够显著抑制肝脏CYP17A1和PXR表达。

法尼醇X受体治疗非酒精性脂肪性肝病研究进展

非酒精性脂肪性肝病(NAFLD)是代谢综合征的肝脏表现,其主要表现为肝脂肪变性。近年来法尼醇X受体(FXR)被发现参与胆汁酸、糖脂代谢,抑制炎症参与碳水化合物的代谢,被认为是一类有治疗前景的药物治疗靶点。