背景:脂肪肝(FLD)在全球范围内引起了重大的全球健康关注,将其分为非酒精性脂肪性肝病(NAFLD)和酒精性脂肪性肝病(AFLD)取决于是否存在慢性和过度饮酒。在疾病的各个阶段缺乏针对FLD的特定治疗干预措施,使得其治疗异常艰巨。尽管FLD和高脂血症密切相关,关于降脂药物如何影响FLD仍存在争议.前蛋白转化酶枯草杆菌蛋白酶/Kexin9型(PCSK9)是一种主要在肝脏中合成的丝氨酸蛋白酶,这对胆固醇稳态有至关重要的影响。研究证实,PCSK9抑制剂具有突出的降脂特性和显著的临床疗效,从而证明需要进一步探索其在FLD中的潜在作用。
目的:通过全面的文献检索,本文就PCSK9、脂质代谢与FLD的关系及相关机制进行综述。此外,它将评估PCSK9抑制剂(包括天然存在的PCSK9抑制剂,例如常规草药),用于治疗FLD,并作为更新此类疾病的治疗方案的指南。
方法:使用几个电子数据库进行了全面的文献检索,包括Pubmed,Medline,Embase,CNKI,万方数据库和ClinicalTrials.gov,从数据库成立到2024年1月30日。文献检索中使用的关键词是“脂肪肝”,“肝脂肪变性”,\"PCSK9\",“中药”,“草药”,“植物药”,“临床试验”,\"vivo\",\“体外\”,链接到AND/OR。大多数纳入的研究都在五年之内。
结果:PCSK9通过LDLR依赖性和非依赖性途径参与循环脂质的调节,并且与从头脂肪生成有潜在的联系。主要临床研究表明,循环PCSK9水平与NAFLD的严重程度呈正相关。在暴露于慢性酒精的个体中观察到循环PCSK9水平升高。许多研究已经证明PCSK9抑制剂改善非酒精性脂肪性肝炎(NASH)的潜力,可能完全缓解肝脏脂肪变性,减少肝功能损害。在动物实验中,PCSK9抑制剂在减轻酒精性诱导的肝脏脂质积累和肝炎方面表现出功效。中药如黄连素,姜黄素,白藜芦醇,piceatannol,sauchinone,羽扇豆,槲皮素,红景天苷,银杏内酯,丹参酮,Lunasin,卡佩拉布萨·巴斯特里斯,gypenosides,桑叶是主要的天然PCS9抑制剂。令人兴奋的是,通过抑制转录,减少分泌,直接靶向和其他途径,中药对PCSK9发挥抑制作用,从而发挥潜在的FLD治疗作用。
结论:PCSK9在FLD的发展中起重要作用,PCSK9抑制剂在临床前和临床研究中都显示出对血脂调节和FLD的有益作用。此外,一些中药通过抑制PCSK9和抗炎、抗氧化作用改善了FLD的病情进展。因此,抑制PCSK9似乎是一种有希望的FLD治疗策略.
BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD.
OBJECTIVE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions.
METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were \"fatty liver\", \"hepatic steatosis\", \"PCSK9\", \"traditional Chinese medicine\", \"herb medicine\", \"botanical medicine\", \"clinical trial\", \"vivo\", \"vitro\", linked with AND/OR. Most of the included studies were within five years.
RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects.
CONCLUSIONS: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.