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。     

去脂软肝方对非酒精性脂肪性肝炎大鼠FXR-FGF19通路的影响

目的 观察去脂软肝方对非酒精性脂肪性肝炎(NASH)模型大鼠法尼醇X受体(FXR)-成纤维细胞因子19(FGF19)通路的影响。方法 雄性SD大鼠随机分为正常组(Control组,n=8)、模型组(HFD组,n=12)、辛伐他汀组(Simvastatin组,n=8)、去脂软肝方高剂量组(QH组,n=8)、去脂软肝方低剂量组(QL组,n=8),Control组给予普通饲料喂养,其余组高脂饲料喂养。10周末取材,观察大鼠肝脏病理切片变化,检测各组血清肝功能指标、肝脏与小肠FGF19、肝脏中胆汁酸(BA)。检测小肠FXR、肝脏胆固醇7α-羟化酶(CYP7A1)表达情况。多组间比较采用单因素方差分析,进一步两组间比较采用LSD-t检验。结果 与Control组相比,HFD组病理表现出明显炎性病变和脂肪变性。与HFD组相比,各用药组的HDL-C显著升高,ALT、AST、TC、TG、LDL-C均显著下降(P值均<0.05)。与Control组相比,HFD组大鼠小肠FGF19显著下降、肝脏BA显著升高(P值均<0.05)。与HFD组相比,各用药组的小肠中FGF19显著升高,肝脏BA显著下...     

非酒精性脂肪性肝炎的药物治疗

非酒精性脂肪性肝炎是非酒精性脂肪性肝病的一种,其可以进一步发展为终末期肝病以致肝功能衰竭。非酒精性脂肪性肝炎药物治疗主要包括二甲双胍、过氧化物酶体增殖物-γ激动剂、已酮可可碱、N-乙酰半胱氨酸、血管紧张素Ⅱ受体拮抗剂、熊去氧胆酸、维生素E、降脂药等。近年来,对这些药物治疗非酒精性脂肪性肝炎的疗效也做了相关研究,但均未得出确切的结论。     

肠道法尼醇X受体在非酒精性脂肪性肝病中的作用机制及相关靶向药物

近年来非酒精性脂肪性肝病(NAFLD)发病率日益剧增,若患者不良生活方式无法及时调整,且临床尚缺乏有效的药物,使得NAFLD的治疗差强人意。法尼醇X受体(FXR)作为胆汁酸的主要受体,通过参与糖、脂代谢来影响NAFLD,而肠道FXR(iFXR)具有局限作用于肠道的优势,可避免全身释放所带来的副作用,在NAFLD的治疗上具有潜在的价值,但也存在一定的争议。综述了近年来iFXR在NAFLD的研究进展。     

非酒精性脂肪性肝炎

非酒精性脂肪性肝炎具有与酒精性肝炎相似的组织学表现，但具有不同的发病机制和预后，本就这两方面作一综述。     

非酒精性脂肪性肝炎的治疗

非酒精性脂肪肝可以是一个独立的疾病 ,但更多见于全身性疾患在肝脏的病理过程。肥胖症、药物和毒物中毒、营养不良、糖尿病、妊娠、肝炎病毒或其他病原体感染以及先天性代谢缺陷等都可引起非酒精性脂肪肝。·本病在组织学上有与酒精性肝病类似的表现 ,肝活检显示从轻度的脂肪性肝炎至重度肝纤维化和肝硬化不同的组织学特征。·非酒精脂肪性肝炎诊断一般依据Ｐｏｗｅｌｌ等建议的标准 ,即①肝活检标本显示伴有炎症的中～重度大泡性脂肪变性 ,可伴或不伴有Ｍａｌｌｏｒｙ小体、纤维化或肝硬化 ;②无饮酒史或饮酒每周 <4 0克 ,随机检测血乙醇…     

非酒精性脂肪性肝炎的研究进展

一、非酒精性脂肪性肝炎（ＮＡＳＨ）及其病因学、流行病学早在１９世纪末,病理学家就发现脂肪肝和肝硬化之间存在某种联系,虽然,当时酒精是致脂肪肝的最主要的病因。后又发现除酒精因素外,仍有一部分病人会发生脂肪性肝炎甚至肝纤维化,且似乎在女性、肥胖和糖尿病病人中好发,当时曾用“脂肪性肝炎”［１］、“脂肪坏死”、“糖尿病肝炎”［２］来描述。而后又发现用空回肠旁路手术治疗肥胖症后可出现与酒精性肝病相类似的病理改变,即：肝细胞脂肪变性、小叶和汇管区炎症,有时亦可有Ｍａｌｌｏｒｙ小体形成和肝纤维化等［３］。这个…     

非酒精性脂肪性肝炎治疗新靶点和分子靶向药物

近年来,随着对非酒精性脂肪性肝炎（NASH）发病机制研究的深入,在新靶点和分子靶向药物研究方面取得了较大的进展,动物实验及临床试验均显示了这些药物的良好应用前景。本文将主要介绍选择性外周大麻素受体阻滞剂、过氧化物酶体增殖物活化受体（PPAR）α/δ双激动剂、法尼酯衍生物X受体（FXR）激动剂、Caspase抑制剂和磷酸二脂酶4选择性抑制剂等在NASH治疗中的进展。     

Role of farnesoid X receptor in cholestasis

The nuclear receptor farnesoid X receptor (FXR) plays an important role in physiological bile acid synthesis, secretion and transport. Defects of FXR regulation in these processes can cause cholestasis and subsequent pathological changes. FXR regulates the synthesis and uptake of bile acid via enzymes. It also increases bile acid solubility and elimination by promoting conjugation reactions and exports pump expression in cholestasis. The changes in bile acid transporters are involved in cholestasis, which can result from the mutations of transporter genes or acquired dysfunction of transport systems, such as inflammation‐induced intrahepatic cholestasis. The modulation function of FXR in extrahepatic cholestasis is not identical to that in intrahepatic cholestasis, but the discrepancy may be reduced over time. In extrahepatic cholestasis, increasing biliary pressure can induce bile duct proliferation and bile infarcts, but the absence of FXR may ameliorate them. This review provides an update on the function of FXR in the regulation of bile acid metabolism, its role in the pathophysiological process of cholestasis and the therapeutic use of FXR agonists.     

Pathophysiology guided treatment of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease is a spectrum that ranges from benign steatosis to steatohepatitis. It has become the most common cause of chronic liver disease, and yet there continues to be a lack of effective therapeutic options. This article reviews current concepts underlying the pathophysiological basis of nonalcoholic steatohepatitis from development of insulin resistance to the establishment of fibrosis. Then using a physiology-based approach, specific targeted therapeutics are reviewed along with their drawbacks. The evidence behind current therapies is based predominantly on small trials and, thus, no recommendations can be made until larger randomized trials are conducted.     

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.     

Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis

A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, was diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BMI) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene.     

Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease.