Ahsan Farah, Oliveri Federico, Goud Harshit K, Mehkari Zainab, Mohammed Lubna, Javed Moiz, Althwanay Aldanah, Rutkofsky Ian H
Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Cardiology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Cureus. 2020 Sep 14;12(9):e10446. doi: 10.7759/cureus.10446.
Statins, the lipid-lowering drugs, and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), a lipid-related pathology, share a complex relationship, one known to be hepatotoxic and other being hepatic injury. NASH is an unresolved mystery in terms of treatment. Could statins prove to be a promising solution due to their pleiotropic properties in addition to the cholesterol-lowering effect? This study aims to find statin effectiveness in NAFLD/NASH treatment and prevention of associated adverse outcomes. An extensive data search was done to identify the studies assessing statin effect on NAFLD/NASH and then analyzed to establish the relationship. Several studies demonstrated a reduction in NAFLD/NASH-associated inflammation and fibrosis with statin treatment. These anti-inflammatory and anti-fibrotic effects were through their pleiotropic properties, which were in addition to their cholesterol-lowering effect. In various animal studies, statins were found to improve hepatic lipotoxicity, oxidative stress, inflammatory responses, and fibrosis associated with NASH through multiple pathways. Statins exert these protective effects by recovering the gene expression level of peroxisomal proliferator-activated receptor alpha (PPARα) and therefore restore the mitochondrial and peroxisomal fatty acid oxidation (FAO). Statin treatment also increased the levels of paraoxonase 1 (PON1), an antioxidant and antiatherogenic enzyme that is reduced in NAFLD as well as encounter the hepatic lipotoxicity by resolving cholesterol crystals and Kupffer cells (KCs) with crown-like structures (CLSs). They exhibited antitumor properties by inhibiting proinflammatory cytokines and vascular proliferative factors. Moreover, they restored a healthy liver sinusoidal endothelial cell (LSEC) and hepatic stellate cells (HSC) along with inhibiting the activation of HSC via modulating inducible nitric oxide synthase (iNOS) and expressions of endothelial nitric oxide synthase (eNOS). Besides, they were protective against cardiovascular disease (CVD)-related morbidity and mortality, hepatocellular carcinoma (HCC), and metabolic syndrome (MS) associated with NAFLD/NASH. NASH and its precursor, NAFLD, could be treated and prevented with statins owing to their pleiotropic properties. This study helps to prove this by looking back at different literature and has successfully enlightened the point. Once proved through large clinical trials on humans, it could revolutionize the NASH therapy.
他汀类药物作为降脂药物，与非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎（NASH）这一脂质相关病理状态存在复杂关系，前者已知具有肝毒性，后者则是肝损伤。NASH在治疗方面仍是一个未解之谜。鉴于他汀类药物除了具有降胆固醇作用外还具有多效性，它们能否成为一种有前景的解决方案呢？本研究旨在探寻他汀类药物在NAFLD/NASH治疗及预防相关不良结局方面的有效性。通过广泛的数据检索来确定评估他汀类药物对NAFLD/NASH影响的研究，然后进行分析以确立两者关系。多项研究表明，他汀类药物治疗可减轻NAFLD/NASH相关的炎症和纤维化。这些抗炎和抗纤维化作用是通过其多效性实现的，这是除降胆固醇作用之外的额外效果。在各种动物研究中，发现他汀类药物可通过多种途径改善与NASH相关的肝脂毒性、氧化应激、炎症反应和纤维化。他汀类药物通过恢复过氧化物酶体增殖物激活受体α（PPARα）的基因表达水平来发挥这些保护作用，从而恢复线粒体和过氧化物酶体的脂肪酸氧化（FAO）。他汀类药物治疗还可提高对氧磷酶1（PON1）的水平，这是一种抗氧化和抗动脉粥样硬化酶，在NAFLD中水平降低，并且通过溶解胆固醇晶体和具有冠状结构（CLS）的库普弗细胞（KC）来对抗肝脂毒性。它们通过抑制促炎细胞因子和血管增殖因子表现出抗肿瘤特性。此外，它们通过调节诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的表达，恢复健康的肝窦内皮细胞（LSEC）和肝星状细胞（HSC），同时抑制HSC的激活。此外，它们对与NAFLD/NASH相关的心血管疾病（CVD）发病率和死亡率、肝细胞癌（HCC）以及代谢综合征（MS）具有保护作用。由于他汀类药物具有多效性，NASH及其前驱病变NAFLD可以用他汀类药物进行治疗和预防。本研究通过回顾不同文献有助于证明这一点，并成功阐明了这一观点。一旦通过针对人类的大型临床试验得到证实，则可能彻底改变NASH的治疗方法。
