Inflammation: The Straw That Broke the NAFLD Liver!
Inflammation: The Straw That Broke the NAFLD Liver!
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DOI：
10.1016/j.jcmgh.2022.01.006
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发表时间：
2022
影响因子：
7.2
通讯作者：
Raeman, Reben
中科院分区：
文献类型：
--
作者：
Raeman, Reben
非酒精性脂肪性肝病（NAFLD）是一系列疾病，范围从良性非酒精性脂肪肝（NAFL）或轻度脂肪变性到更严重的非酒精性脂肪性肝炎（NASH），其特征在于过度炎症和不同程度的纤维化。1估计20%-25%的NAFL患者进展为NASH，高达25%的NASH患者进展为肝硬化。1目前，NASH相关肝硬化是美国肝移植的第二大适应症，NASH患者患肝细胞癌的风险增加。1尽管在过去的二十年里，对NAFLD自然史的理解取得了进展，但研究人员仍在努力确定NAFL进展为NASH以及随后肝硬化发展背后的细胞和分子机制。在下文中，我提供的证据表明，脂肪变性本身不足以驱动NAFLD进展，并主张NASH发病机制的多重打击模型，其中各种宿主内源性和外源性损伤促进肝脏炎症，加速NAFLD进展。NAFL的特征在于在没有炎症或肝损伤的情况下，脂肪酸作为三酰甘油在肝细胞中积累。1当肝脏脂肪酸摄取和/或合成超过脂肪酸催化剂通过脂肪酸氧化和输出为极低密度脂蛋白时，观察到肝细胞中的脂肪沉积或肝脂肪变性。2与脂肪细胞不同，肝细胞在稳态条件下不储存脂肪酸。然而，由于胰岛素抵抗，循环游离脂肪酸升高，因为胰岛素不能充分抑制脂肪组织脂解。这增加了肝细胞中的脂肪酸摄取，导致肝脂肪酸沉积的净增加。2虽然导致NAFLD中肝脂肪酸积累的确切分子机制和事件顺序尚未完全了解，但胰岛素抵抗被认为是脂肪肝的主要驱动因素。3肝脏胰岛素抵抗通过促进从头脂肪生成来阻止肝脏葡萄糖产生的抑制，从而导致高血糖症、代偿性高胰岛素血症增加和肝细胞中脂肪酸沉积。3脂肪肝通过破坏肝脏代谢损害肝功能，在某些情况下导致肝细胞凋亡，这被认为有助于促进NAFLD中脂毒性诱导的肝脏炎症。3但鉴于细胞凋亡是一种非溶解性、非炎症性细胞死亡途径，对周围细胞的影响有限，脂肪变性诱导的肝细胞凋亡可能不会对NAFLD中的肝脏炎症产生实质性影响。4来自动物研究的证据表明，肝细胞中脂肪酸蓄积是保护组织免受脂肪酸相关脂毒性的机制。5此外，脂肪肝动物模型，其中高脂肪饮食或瘦素缺乏导致大量脂肪变性，但不是脂肪性肝炎，表明脂肪肝可能不会推动NAFLD进展。6这一点得到了临床证据的进一步证实，即大部分NAFL人群（占总人群的20%-30%，肥胖人群高达75%-100%）要么是缓慢进展者，要么是非进展者。因此，从临床角度来看，NAFL被认为是一种良性疾病，不需要临床干预。强调NAFLD的代谢基础导致了一个连续的“两次打击”模型的建议，以解释NAFLD患者的疾病进展。“二次打击”模型表明，肝脏脂质积累提供了...
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of conditions ranging from benign nonalcoholic fatty liver (NAFL) or bland steatosis to the more severe nonalcoholic steatohepatitis (NASH), characterized by excessive inflammation and varying degrees of fibrosis. 1 An estimated 20%–25% of patients with NAFL progress to NASH, and up to 25% of patients with NASH progress to cirrhosis. 1 Currently, NASH-related cirrhosis is the second leading indication for liver transplantation in the United States, and patients with NASH face an increased risk of developing hepatocellular carcinoma. 1 Despite the progress in understanding of the natural history of NAFLD over the last two decades, researchers continue to struggle in identifying the cellular and molecular mechanisms behind the progression of NAFL to NASH and the subsequent development of cirrhosis. In the following, I provide evidence suggesting that steatosis alone is insufficient to drive NAFLD progression, and argue for a multiple-hit model of NASH pathogenesis wherein various host-intrinsic and extrinsic insults promote hepatic inflammation fueling NAFLD progression. NAFL is characterized by accumulation of fatty acids as triacylglycerol in hepatocytes in the absence of inflammation or liver injury. 1 Fat deposition in hepatocytes or hepatosteatosis is observed when hepatic fatty acid uptake and/or synthesis exceeds fatty acid catabolism via fatty acid oxidation and export as very low-density lipoproteins. 2 Unlike adipocytes, hepatocytes do not store fatty acids under homeostatic conditions. However, with insulin resistance, circulating free fatty acids are elevated because insulin does not sufficiently inhibit adipose tissue lipolysis. This increases fatty acid uptake in the hepatocyte resulting in a net increase in hepatic fatty acid deposition. 2 Although the precise molecular mechanisms and sequence of events leading to hepatic fatty acid accumulation in NAFLD are not well understood, insulin resistance is considered the primary driver of hepatosteatosis. 3 Hepatic insulin resistance prevents suppression of hepatic glucose production contributing to hyperglycemia, increased compensatory hyperinsulinemia, and fatty acid deposition in hepatocytes by promoting de novo lipogenesis. 3 Hepatosteatosis compromises liver function by disrupting hepatic metabolism and in some instances causing hepatocyte apoptosis, which was deemed instrumental in promoting lipotoxicity-induced hepatic inflammation in NAFLD. 3 But given that apoptosis is a nonlytic, noninflammatory cell death pathway that has limited effects on the surrounding cells, steatosis-induced hepatocyte apoptosis may not substantially impact hepatic inflammation in NAFLD. 4 Evidence from animal studies suggests that fatty acid accumulation in hepatocytes is a mechanism to protect tissues from fatty acid–associated lipotoxicity. 5 Furthermore, animal models of hepatosteatosis where a high-fat diet or leptin deficiency resulted in substantial steatosis but not steatohepatitis suggest that hepatosteatosis may not drive NAFLD progression. 6 This was further corroborated by clinical evidence that a large proportion of the population with NAFL, which represents 20%–30% of the general population and as high as 75%–100% of obese individuals, are either slow progressors or nonprogressors. 1 As such, from a clinical perspective, NAFL is considered a benign condition that does not require clinical intervention. Emphasis on the metabolic underpinnings of NAFLD led to the proposal of a sequential “two-hit” model to explain disease progression in patients with NAFLD. The “two-hit” model suggests that hepatic lipid accumulation provides …
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影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.
DOI：
10.1038/s41575-018-0011-z
发表时间：
2018-07
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Tripathi A;Debelius J;Brenner DA;Karin M;Loomba R;Schnabl B;Knight R
通讯作者：
Knight R
影响因子：
5
作者：
Kaden-Volynets, Valentina;Basic, Marijana;Bischoff, Stephan C.
通讯作者：
Bischoff, Stephan C.
影响因子：
13.5
作者：
Chalasani, Naga;Younossi, Zobair;Sanyal, Arun J.
通讯作者：
Sanyal, Arun J.
影响因子：
13.5
作者：
Yamaguchi, Kanji;Yang, Liu;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae