Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease
Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease
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DOI：
10.1007/978-981-10-8684-7_3
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Chitturi, Shivakumar
中科院分区：
文献类型：
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作者：
Farrell, Geoffrey C.;Haczeyni, Fahrettin;Chitturi, Shivakumar
营养过剩，通常与肥胖和遗传易感性，导致胰岛素抵抗，这是一个不变的伴随非酒精性脂肪肝疾病（NAFLD）。非酒精性脂肪性肝炎（NASH）的相关代谢异常、糖尿病前期或已确诊的糖尿病、高血压和致动脉粥样硬化性血脂异常（聚集为代谢综合征）往往更严重，表明其是代谢发病机制的一部分。肝细胞损伤和小叶炎症的起源将NASH与简单的脂肪变性区分开来，这引起了研究人员的兴趣，但现在广泛接受NASH是由肝脏脂毒性引起的。关键问题不是肝脏脂肪的数量，而是积累的脂质分子的类型，以及它们如何“包装”以避免亚细胞损伤。可能的脂毒性介质包括游离（未酯化）胆固醇、饱和游离脂肪酸、二酰基甘油、溶血磷脂酰胆碱、鞘脂和神经酰胺。脂滴是细胞内储存非结构脂质的细胞器，其调节受遗传多态性如PNPLA3的影响。不能隔离化学反应性脂质分子的细胞经历线粒体损伤、内质网（ER）应激和自噬，所有这些过程都是NASH发病机制所关注的。脂毒性通过细胞凋亡（一种高度调节的非炎性细胞死亡形式）以及坏死、坏死性凋亡和焦亡杀死肝细胞;后者涉及线粒体损伤、氧化应激、c-Jun N-末端激酶（JNK）活化和释放c-Jun相关分子模式（DAMP）。DAMP通过结合模式识别受体（例如Toll样受体4（TLR4）和NOD样受体蛋白3（NLRP 3）炎性体）刺激先天免疫，所述炎性体释放促炎趋化因子和细胞因子的级联。因此，脂毒性肝细胞损伤吸引炎性细胞，特别是活化的巨噬细胞，其作为冠状结构包围气球样肝细胞。在实验和人类NASH中，肝脏都含有胆固醇晶体，这是NLRP 3激活的第二个信号;这导致白细胞介素（IL）-1 β和IL 18分泌，以吸引和激活巨噬细胞和中性粒细胞。损伤的肝细胞还释放质膜衍生的细胞外囊泡;这些囊泡已被证明在NASH中循环并且是促炎性的。代谢功能障碍导致脂毒性、先天性免疫反应和由此产生的肝脏细胞炎症模式的方式也可能与肝纤维化和肝癌发生有关。精确定位参与NASH的关键分子最终将导致针对NASH的有效药物治疗。
Overnutrition, usually with obesity and genetic predisposition, lead to insulin resistance, which is an invariable accompaniment of nonalcoholic fatty liver disease (NAFLD). The associated metabolic abnormalities, pre- or established diabetes, hypertension and atherogenic dyslipidemia (clustered as metabolic syndrome) tend to be worse for nonalcoholic steatohepatitis (NASH), revealing it as part of a continuum of metabolic pathogenesis. The origins of hepatocellular injury and lobular inflammation which distinguish NASH from simple steatosis have intrigued investigators, but it is now widely accepted that NASH results from liver lipotoxicity. The key issue is not the quantity of liver fat but the type(s) of lipid molecules that accumulate, and how they are "packaged" to avoid subcellular injury. Possible lipotoxic mediators include free (unesterified) cholesterol, saturated free fatty acids, diacylglycerols, lysophosphatidyl-choline, sphingolipids and ceramide. Lipid droplets are intracellular storage organelles for non-structural lipid whose regulation is influenced by genetic polymorphisms, such as PNPLA3. Cells unable to sequester chemically reactive lipid molecules undergo mitochondrial injury, endoplasmic reticulum (ER) stress and autophagy, all processes of interest for NASH pathogenesis. Lipotoxicity kills hepatocytes by apoptosis, a highly regulated, noninflammatory form of cell death, but also by necrosis, necroptosis and pyroptosis; the latter involve mitochondrial injury, oxidative stress, activation of c-Jun N-terminal kinase (JNK) and release of danger-associated molecular patterns (DAMPs). DAMPs stimulate innate immunity by binding pattern recognition receptors, such as Toll-like receptor 4 (TLR4) and the NOD-like receptor protein 3 (NLRP3) inflammasome, which release a cascade of pro-inflammatory chemokines and cytokines. Thus, lipotoxic hepatocellular injury attracts inflammatory cells, particularly activated macrophages which surround ballooned hepatocytes as crown-like structures. In both experimental and human NASH, livers contain cholesterol crystals which are a second signal for NLRP3 activation; this causes interleukin (IL)-1 beta and IL18 secretion to attract and activate macrophages and neutrophils. Injured hepatocytes also liberate plasma membrane-derived extracellular vesicles; these have been shown to circulate in NASH and to be pro-inflammatory. The way metabolic dysfunction leads to lipotoxicity, innate immune responses and the resultant pattern of cellular inflammation in the liver are likely also relevant to hepatic fibrogenesis and hepatocarcinogenesis. Pinpointing the key molecules involved pharmacologically should eventually lead to effective pharmacotherapy against NASH.