AMPK激活在非酒精性脂肪性肝病中的研究进展

非酒精性脂肪性肝病(NAFLD)的发生和进展与脂质积累、胰岛素抵抗、炎症、肝损伤、纤维化等因素有关。AMP依赖蛋白激酶(AMPK)是调控生物能量代谢的关键分子, 参与调控脂质代谢、自噬、炎症和细胞凋亡等众多生物过程。促进AMPK激活可减轻肝脏脂质积累和胰岛素抵抗, 缓解NAFLD的发展, 减轻肝脏炎症和纤维化抑制NAFLD向非酒精性脂肪性肝炎进展。     

肝窦内皮细胞与非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一个与代谢综合征相关的日益扩大的健康问题.肝窦内皮细胞(liver sinusoidal endothelial cells,LSECs)是位于血液与其他肝细胞类型之间高度专业化的内皮细胞,由窗孔组成,具有高内吞能力,并在维持肝脏整体稳态中发挥重要作用.病理条件下LSECs可能是多种慢性肝病的关键事件.本篇综述介绍了LSECs的独特生理结构和功能,重点总结了NAFLD中LSECs的主要变化(包括肝窦毛细血管化、血管生成、血管收缩、促炎和促纤维化)及其发生机制,还涉及LSECs对NAFLD进展的影响,旨在说明LSECs靶向治疗对NAFLD具有潜在疗效.     

从非酒精性脂肪性肝病到代谢相关脂肪性肝病的变迁

非酒精性脂肪性肝病(NAFLD)是全球范围最常见的慢性肝病,且进展至肝纤维化、肝硬化、肝癌等不良结局加重社会医疗负担。NAFLD特征是肝脏脂肪沉积和炎症,近40余年以来一直是一个排他性诊断,随着研究不断地深入,2020至2023年期间经历了两次更名,从代谢相关脂肪性肝病(MAFLD)到代谢功能障碍相关脂肪性肝病(MASLD)。本文讨论了目前对NAFLD/MAFLD/MASLD特征的对比、临床和研究问题,旨在提高我们对脂肪性肝病(SLD)的全面理解。     

非酒精性脂肪性肝病的肝脏芯片模型

非酒精性脂肪性肝病(NAFLD)是遗传易感和胰岛素抵抗引起的代谢功能障碍相关脂肪性肝病,肝脏特征性病变包括大泡性肝脂肪变、小叶内炎症、肝细胞气球样变以及肝纤维化。随着肥胖、2型糖尿病和代谢综合征的流行,NAFLD已成为全球最常见的慢性肝病,其与肝硬化、肝癌和肝衰竭密切相关[1]。     

中药治疗非酒精性脂肪性肝病的作用机制

非酒精性脂肪性肝病(NAFLD)是全球范围内最重要的肝病之一,中药治疗NAFLD疗效显著,其作用机制与改善脂质代谢、减轻肝脏炎症、调节肠道菌群、改善先天免疫和抗肝纤维化等有关。总结了目前中药治疗NALFD作用机制的现有数据,以期为临床应用提供参考。     

肥胖症肝病理学表现

在发达国家,肥胖相关肝病,特别是非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)已较为常见,它们是肝脏代谢综合征的表现。NASH可导致进展性肝纤维化、肝硬化和终末期肝病,并增加肝细胞肝癌(HCC)的发生。肝活检仍是观察、评估、分期和分级NASH的金标准。已证明手术或药物减重可减轻肝脏炎症反应、使肝纤维化逆转,某些情况下甚至使患者肝硬化逆转。在治疗前和手术中进行肝活检可评估脂肪性肝炎及其分级和分期。一、NAFLD和NASH1999年,Matteoni等[1]将NAFLD分类为:Ⅰ型,单纯脂肪肝;Ⅱ型,脂肪肝+非特异性炎症;Ⅲ型,脂肪肝…     

肝窦内皮细胞与肝纤维化的关系

生理情况下，肝窦内皮细胞(LSEC)对肝脏稳态的维持起重要作用。而在肝脏病理损伤条件下,LSEC可通过改变其自身结构即毛细血管化对损伤做出反应，并加重肝损伤。此外,LSEC与肝脏中其他细胞的相互作用对肝纤维化的发生发展也有一定作用，其中与肝纤维化的主要效应细胞——肝星状细胞的交互作用占主体地位。本文主要阐述慢性肝损伤时LSEC在肝纤维化发生发展中的作用。     

基于肠-肝轴理论探讨非酒精性脂肪性肝病和肠道菌群的关系

非酒精性脂肪性肝病(NAFLD)目前已成为最主要的慢性肝病,被认为是代谢综合征的肝脏表现,后期可能向肝纤维化及肝硬化,甚至是肝癌发展。肠道菌群作为人体重要的共生物,影响人体的代谢功能,可能和NAFLD的发病密切相关。肠-肝轴理论为"肠道菌群失调可引起肝脏改变"提供了理论基础。探讨了肠道菌群和NAFLD发病的关系,为后期研究肠道菌群靶向治疗NAFLD奠定理论基础。     

非酒精性脂肪性肝病与肠道微生态

<正>随着肥胖和代谢综合征(MS)的流行,非酒精性脂肪性肝病(NAFLD)的发病率逐渐上升,已成为我国最常见的慢性肝病^[1]。NAFLD发病机制是基于“二次打击”假说而提出的“多重打击”假说^[2]。近些年,有新的观点认为肠道菌群(intestinal microecology,IM)与NAFLD密切相关。在动物模型研究发现,肠道微生态失衡可以导致肝脏脂肪变性、炎症、甚至肝纤维化等。根据肠-肝轴理论,肠道微生态平衡被破坏时,有害的肠道细菌及其代谢产物能够通过门脉系统进入肝脏,造成机体免疫应答和炎症反应,进而导致NAFLD的发生和发展^[3]。     

非酒精性脂肪性肝病与代谢综合征

非酒精性脂肪性肝病(NAFLD)事实上是一个肝脏脂肪性病变的疾病谱,包括单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、肝纤维化或肝硬化、肝衰竭,甚至部分患者发生肝细胞性肝癌。NAFLD与代谢综合征(MS)密切伴随,并认为是代谢综合征的肝脏表现。胰岛素抵抗可能是二者共同的发病基础。NAFLD已经成为MS、2型糖尿病(T2DM)和心血管疾病(CVD)的重要的独立预测因子,NAFLD成为T2DM和CVD高危人群,因此早期诊断和早期干预NAFLD对预防T2DM和CVD具有重要意义。     

Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis,cirrhosis and hepatocellular carcinoma

Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed.In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.     

脂毒性在非酒精性脂肪性肝病发生发展中的作用

非酒精性脂肪性肝病(NAFLD)目前是体检时肝脏生化学指标异常的首要原因,但其发生发展的机制仍不十分明确,尚缺乏有效的治疗方法。简述了脂毒性通过触发肝脏内质网应激、细胞死亡、炎症三种病理反应驱动NAFLD向非酒精性脂肪性肝炎、肝硬化的发生及转化,认为脂毒性是促进NAFLD向炎症、纤维化发展的重要因素,为NAFLD的防治提供一种新的途径。     

Role of liver biopsy and serum markers of liver fibrosis in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is common and may progress to end-stage liver disease. Liver-related morbidity and mortality occur almost exclusively in patients whose disease progresses to advanced fibrosis and cirrhosis. Presence and severity of liver fibrosis seem the most important indicators of long-term prognosis. Clinical and biochemical variables may help select NAFLD patients in whom liver biopsy may provide the most prognostic information. Some serum markers of liver fibrosis and imaging techniques aimed at measuring liver stiffness are under investigation as tools to determine severity of liver fibrosis in patients who have NAFLD, but none of them yet can replace liver biopsy.     

Liver fibrosis in non-alcoholic fatty liver disease-diagnostic challenge with prognostic significance

Non-alcoholic fatty liver disease(NAFLD) is the mostcommon liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis(stage F3) and cirrhosis(stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers(e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques(transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.     

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.     

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.     

Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research

Nonalcoholic fatty liver disease (NAFLD) results in histologically complex specific and nonspecific injury patterns. In clinical research of NAFLD, the liver biopsy evaluation provides a wealth of information on the architectural arrangement and severity of a variety of histologic changes, including steatosis, inflammation, cellular injury, and fibrosis. This information is summarized as an overall diagnostic category, such steatosis or steatohepatitis and the severity of the injury can be graded and staged. Histopathologic disease classification in NAFLD is related to but separate from evaluation of individual histologic lesions. The patient population under study may affect the prevalence of histologic findings and in particular, pediatric patients with NAFLD may show a higher prevalence of zone 1 steatosis and periportal fibrosis as compared with adult populations. For the purposes of clinical research, it is important to provide the pathologist with biopsies that are adequate to classify the disease process as well as to grade and stage the changes. A current understanding of NAFLD pathologic classification, as well as nuances of grading and staging, is presented in this review.     

The role of liver sinusoidal endothelial cells in liver remodeling after injury

Liver transplantation is the optimal treatment for patients with end-stage liver disease, metabolic liver diseases, and hepatic malignancies that are not amenable to resection. Hepatic ischemia-reperfusion injury (IRI) is the main problem in liver transplantation and liver resection, leading to parenchymal cell injury and organ dysfunction. The damage of liver sinusoidal endothelial cells (LSECs) is a critical event in IRI. LSECs work as an important regulating factor of liver regeneration after partial hepatectomy. This review primarily describes the mechanisms of LSECs injury in IRI and explores the roles of LSECs in liver regeneration, and briefly introduces the protective strategies targeting LSECs damaged in IRI.     

Histopathology of nonalcoholic fatty liver disease

Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease(NAFLD) are measured.Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD,i.e.nonalcoholic steatohepatitis(NASH) and fibrosis.Included in the lesions of NAFLD are steatosis,lobular and portal inflammation,hepatocyte injury in the forms of ballooning and apoptosis,and fibros...